Available online at www.sciencedirect.com
ScienceDirect Expanding roles of neutrophils in aging hosts Ching Wen Tseng1,2 and George Y Liu1,2 Neutrophils’ role in the clearance of pathogens is well documented, but there is increasing appreciation that neutrophils can participate in the resolution of infection and inflammation. An obvious implication is that alteration of neutrophil functions with old age could significant impact both susceptibility of the host to infection and inflammatory conditions. Advances in recent years suggest additional chinks in the neutrophil antimicrobial arsenals in aged hosts, which render neutrophils less capable of killing pathogens. Moreover there is evidence that changes in neutrophil cross-talk with other immune cells also contribute to poor resolution of inflammation. These advances provide new insight on how these phagocytic cells could contribute to age-related diseases. Addresses 1 Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States 2 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States Corresponding author: Liu, George Y ([email protected])
Current Opinion in Immunology 2014, 29:43–48 This review comes from a themed issue on Immune senescence Edited by Tamas Fu¨lo¨p and Ruth Montgomery
0952-7915/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coi.2014.03.009
Introduction Neutrophils were once viewed as phagocytic cells packed with antimicrobial substances programmed solely to kill pathogens. After elimination of the microbes from the infection site, they are removed to bring the infection to a resolution. Exciting advances in recent years have altered this simplistic view of neutrophils [1–4]. Added to the phagocytes’ arsenals are neutrophil extracellular DNA traps (NETs) which immobilize bacteria. Neutrophil subsets with either pro-inflammatory or anti-inflammatory properties have been characterized. Additionally, an abundance of data suggests that neutrophils are active players in the orchestration of host defense and resolution of inflammation. These novel findings have provided a more dynamic framework to reevaluate the role of neutrophils in age-related diseases. In this review, we summarize recent developments in the neutrophil and aging field (Figure 1), and discuss their www.sciencedirect.com
significance in the context of the new neutrophil biology and age-related diseases (Table 1). Because of space limitation, the reader is referred to many excellent reviews on the impact of aging on neutrophils [5–13].
Recruitment to the site of inflammation It is well documented that aged individuals are more susceptible to infection. This is unlikely the effect of aging on myelopoiesis since the numbers of circulating neutrophils at baseline and during acute inflammation are not reduced in elderly hosts (reviewed in [13]). Instead, defects in neutrophil recruitment or microbial killing are probably responsible for age-related susceptibility to infection. Neutrophil recruitment is an elaborate process in which circulating neutrophils are attracted to the site of inflammation by following chemokine trails laid out by microbes or host cells [2]. Surface chemokine receptors allow neutrophils to survey chemokine gradients along the vascular endothelium, and subsequent engagement of integrins and CD15 on neutrophils with P-selectin glycoprotein ligand-1 (PSGL-1), and P-selectins, L-selectins and E-selectins, and ICAMs on endothelial cells leads to neutrophil attachment and transmigration. Though defects in neutrophil chemotaxis are well documented in aging hosts, several new studies have provided important insight on how recruitment is compromised with aging. The most interesting report is a study by Sapey and colleagues describing decreased accuracy of neutrophil migration to various inflammatory stimuli without loss of chemokinesis [14]. The authors showed that constitutive activation of phosphoinositide 3-kinase (PI3K) was responsible for the inaccurate migration and inhibition of PI3Kg or d restored accuracy of the directional chemotaxis. In a model of pseudomonas lung infection, inaccurate neutrophil migration was offered as an explanation for the high number of neutrophils stranded in the lung parenchyma of aged mice [15]. By comparison, neutrophils from young mice were primarily recruited to the alveolar space to more effectively combat the infection. Though neutrophil chemotactic deficits are well described in vitro in aged hosts (reviewed in [13]), several reports in the past years have underlined the complexity of neutrophil recruitment in vivo. Three infection studies performed using Staphylococcus aureus or P. aeruginosa reported reduced neutrophil numbers at the infection site [15,16,17]. Impaired neutrophil recruitment could not be explained by local chemokine release as chemokines were found to be more elevated in aged mice in two of the studies [15,16]. Additionally, elevated chemokine Current Opinion in Immunology 2014, 29:43–48
44 Immune senescence
Figure 1
Microbial killing ↓ Phagocytosis ↓ ROS ↓ NETs ↓
Clearance of PMNs, NETs, and DAMPs ? Pro-resolvins and resolvins ?
NETs Apoptotic PMNs
Microbes
Chronic Inflammation ↑
Resolution ↓
Mφ
Endothelial cells
PMNs
↓
Chemotaxis in vitro ↓ in vivo ↓
Bloodstream
Current Opinion in Immunology
PMN functions and senescence. Arrows indicate changes with aging.
receptor (CXCR2) expression on circulating neutrophils did not improve recruitment of the neutrophils in one study [16]. The findings led the authors to suggest that intrinsic defect in CXCR2 signaling likely accounted for the recruitment defect. In contrast to the infectious
stimuli, LPS injection or thermal injury induced higher neutrophil accumulation in aged mice compared to young mice [18,19,20]. Increased expressions of ICAM-1 on lung endothelial cells or E-selectins and P-selectins in the kidneys correlated with neutrophil accumulation and
Table 1 Changes of neutrophil-related functionsin aged hosts
Neutrophil number Neutrophil chemotaxis In vitro In vivo Neutrophil antimicrobial functions Phagocytosis ROS Elastase NETs Clearance of dead neutrophils Clearance of DAMPs or NETs Pro-resolvins, resolvins, or protectins Cytokines Pro-inflammatory Anti-inflammatory Existence of neutrophil types/subsets Pro-inflammatory/promoting tissue injury Anti-inflammatory/protective against tissue injury
Current Opinion in Immunology 2014, 29:43–48
Changes
Comments
$
[12,13]
# #, , or "
[13,14] [15,16,17,18,19,20,36]
# # or $ Variable # Unknown Unknown Unknown
[13] [13] Stimulus dependent [32] [17] # clearance of apoptotickeratinocytes and T cells with aging [38]
# or $ "
Stimulus dependent [17,22,32] [32]
[14,36,50] [19]
Pro-inflammatory MDSCs "with aging [57]
# urinary LXA4 with aging [49]
www.sciencedirect.com
Neutrophils and aging Tseng and Liu 45
were suggested to induce increased neutrophil adhesion [18,20]. However, it remains unclear why infectious and noninfectious stimuli induced different recruitment of neutrophils in young and aged hosts.
Antimicrobial responses Neutrophils from aged host exhibit impaired clearance of pathogens, in addition to chemotactic defects [13]. Normal neutrophil antimicrobial activities include the elaboration of reactive oxygen species (ROS) and antimicrobial proteinases, phagocytosis of invading organisms, and release of NETs [1–3,21]. Many reports suggest that phagocytosis and ROS production are compromised in aged hosts (reviewed in [13]). The underlying mechanisms are not fully understood, but a recent study found reduced glucose accumulation in neutrophils derived from aged individuals in response to TLR1 or TLR4 stimulation. Deficiency in bioenergetics could therefore provide an important explanation for the overall decreased functions of neutrophils with aging [22]. NETs represent a recently described antimicrobial mechanism that is triggered by a variety of pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs) [23]. NETs are chromatin mesh actively expelled by neutrophils as a way to trap pathogens. They promote killing of microbes by bringing the pathogens in close proximity to bound antimicrobial substances and by extending contact between pathogens and antimicrobial proteins. Trapped bacteria are thereby prevented from dissemination into the bloodstream [24]. The mechanism driving NET formation is not completely understood, but C-type lectin receptor mincle, the Raf-MEK-ERK pathway, and NADPH oxidase appear to be important [25– 27]. Deamination of histone by PAD4 drives the disassembly of chromatin, and myeloperoxidase and neutrophil elastase further contribute to the decondensation of chromatin [28,29]. Interestingly, even after extrusion of the NETs, neutrophils can engage in purposeful pursuit and clearance of pathogens [30]. Neutrophils from aged mice produce fewer NETs in response to S. aureus or PMA stimulation [17]. In vivo, fewer NETs are visualized at the site of S. aureus skin infection in aged mice compared to young mice [17], and this partly contributed to increased dissemination of S. aureus into the bloodstream and distant organs. The mechanisms responsible for decreased NET formation in aged hosts are not known, but given the well documented decreased NADPH activity in aged hosts and their involvement in NET formation [26], decreased ROS likely contribute to this age-related change.
Cross-talk with other immune cells Neutrophils perform a variety of functions that complement their antimicrobial activities. They secrete chemokines and cytokines, recruit monocytes, neutrophils, www.sciencedirect.com
and dendritic cells, express MHC class II and costimulatory molecules on their cell surface, induce maturation of DCs, and transport antigens to lymph nodes to support priming of T cells [1]. Increasing evidence suggests that distinct neutrophil subsets exist. In one study, Tsuda and colleagues demonstrated three neutrophil subset phenotypes [31]: PMNs isolated from MRSA-resistant mice that express IL-12 and CCL3 and induce M1 macrophages, PMNs isolated from MRSA-sensitive mice that express IL-10 and CCL2 and activate M2 macrophages, and a third type of PMNs isolated from naı¨ve mice that could convert to either type of neutrophils. The recruitment of the various subsets of neutrophils was therefore suggested to have an influence on the clearance of pathogens. Although neutrophil subsets have not been investigated in aged hosts, recent reports indicated that neutrophils from aged hosts secrete lower levels of chemokines (MIP-2, KC, IL8) and pro-inflammatory cytokine IL6 in response to various stimuli [17,22,32]. Conversely, they produce higher level of IL-10 in response to LPS [32] and show no differences for many of the other cytokines and stimuli surveyed. Cross-talk between neutrophils and other immune cells will be an important area of studies as it promises to shed light on why aged individuals have increased susceptibility to infection and slow resolution and why they exhibit poor adaptive immune response to pathogens and vaccine antigens [33–35].
Resolution versus chronic inflammation Following clearance of pathogens, the next major tasks of the immune system are to remove dead neutrophils, clean off debris, shut down inflammation, and begin the process of healing. Aged individuals exhibit slow healing and have a predilection for chronic inflammatory conditions. Therefore, resolution of inflammation is likely compromised during aging. Arguably, the most important prerequisite to resolution is the clearance of neutrophils. In a burn model, young and aged mice showed similar neutrophil recruitment at an early time point, but the neutrophils persisted longer in aged mice [36], suggesting slower clearance of the phagocytic cells in aged animals. Clearance of apoptotic neutrophils is usually accomplished by macrophages that recognize ‘eat me’ signals displayed on dead neutrophils. Engulfment of apoptotic cells, in turn, induces macrophage to assume an anti-inflammatory phenotype necessary for the resolution of inflammation [37]. Macrophagemediated clearance of apoptotic Jurkat cells and keratinocytes has been shown to be compromised in aged mice based on one study. In that study, the rate of apoptotic cell clearance was dependent on factors present in the serum of aged mice rather than macrophage-intrinsic factors [38]. The study did not specifically address clearance of neutrophils. Clearance of live neutrophils can be enacted by the neutrophils themselves. Recently, studies Current Opinion in Immunology 2014, 29:43–48
46 Immune senescence
in mice and humans have demonstrated that neutrophils can undergo reverse migration, a mechanism that is dependent on downregulation of junctional adhesion molecule JAM-C [39]. Reverse migration could alleviate inflammation from the infection site but has the potential to disseminate inflammation systemically.
suggesting the presence of protective neutrophils [19]. It should be evident that resolution of inflammation is complex and involves close coordination between neutrophils and other immune cells. Further exploration of these mechanisms could provide critical clues on how neutrophils contribute to chronic inflammation.
In addition to PAMPs that are found in abundance during infection, danger-associated molecular patterns (DAMPs) are produced by the host and further amplify the proinflammatory signals. Removal of PAMPs and DAMPs are required to resolve inflammation. Neutrophils express certain proteases, such as matrix metallopeptidase-9 (MMP9), which degrade DAMPS (high-mobility group protein B1 (HMGB1) and heat-shock proteins), preventing their release from damaged cells [40]. Neutrophil MMP9 expression has not been studied in aged subjects, however in response to intracerebral hemorrhage, aged rats exhibit delayed and decreased MMP9 expression from myeloid cells [41]. NETs represent another highly pro-inflammatory substance that must be cleared after infection. They facilitate priming of T cells and have been linked to the induction of autoimmune diseases like Lupus [42–44]. Though they do not induce cytokines on their own, NETs amplify the pro-inflammatory property of LPS [45]. Macrophages derived from human monocytes as well as complement C1q from human sera have been shown to facilitate removal of NETs [45]. NET clearance in old age has not been investigated, though it is clear that macrophages from aged mice show impaired phagocytosis [46].
Perspectives
During the course of infection or inflammation, neutrophils undergo important changes in their lipid profile, turning down pro-inflammatory lipids while up-regulating expression of pro-resolvins, resolvins, and protectins [47,48]. As their names suggest, pro-resolvins, resolvins, and protectins are important molecules that orchestrate the resolution of inflammation or infection. Lipoxin A4 (LXA4), an important pro-resolvin, inhibits FPR1-dependent migration, promotes recruitment of monocytes, and induces phagocytosis of apoptotic neutrophils by macrophages [47,48]. A defect in pro-resolvin or resolvin secretion would explain the proinflammatory predilection of aged hosts. Pertinently, a study of aged individuals demonstrated a decreased urinary level of LXA4 levels [49].
In summary, neutrophils have undergone an image makeover. They have expanded their involvement in all facets of innate and adaptive immunity and in a variety of human diseases. These discoveries should prompt a reevaluation of neutrophil contribution to aging-related diseases.
The outcome of inflammation could also be influenced by the type of neutrophils recruited to fight the infection, as described above. In a systemic Herpes simplex virus infection model, Stout-Delgado and colleagues demonstrated that IL-17 is produced in excess in aged mice leading to accumulation of overactive neutrophils in the liver [50]. Depletion of the neutrophils or neutralization of IL-17 reduced mortality in the aged mice. By contrast, removal of neutrophils in an LPS induced kidney inflammation model led to worsening organ pathology, Current Opinion in Immunology 2014, 29:43–48
Few years ago, Fortin and colleagues reviewed the potential contribution of neutrophils to a number of age-related diseases and lamented on how little has been done in this important field of research [51]. There are now even more compelling reasons to study neutrophils in relation to aging-related diseases. In atherosclerosis, for example, various neutrophil factors have been shown to contribute to the pathology associated with the different phases of atherosclerotic disease [52]. For diabetes, neutrophil elastase has been directly implicated in the mechanism of insulin resistance [53,54]. Perhaps most interestingly are evidence in cancer of two neutrophil-related or myeloid-related cell subsets that have either pro or anti-tumor function [55,56]. The myeloid cell subsets, termed myeloid derived suppressor cells (MDSCs), are a heterogeneous myeloid progenitor population that could be isolated during infection, inflammatory conditions, or cancer. They play an important role in suppression of T cells and in tumor progression [56]. Importantly, one report showed that pro-inflammatory MDSCs are significantly increased with old age [57], and their increased number correlates with the increased incidence of cancer with old age.
Acknowledgements We apologize that we were unable to cite all relevant studies because of space limitation. GYL received grant support from the Telemedicine and Advanced Technology Research Center (TATRC) at the U.S. Army Medical Research and Materiel Command (USAMRMC) under Award No. W81XWH-09-1-0644.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Mayadas TN, Cullere X, Lowell CA: The multifaceted functions of neutrophils. Annu Rev Pathol 2014, 9:181-218.
2.
Kolaczkowska E, Kubes P: Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013, 13:159-175.
3.
Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A: Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012, 30:459-489. www.sciencedirect.com
Neutrophils and aging Tseng and Liu 47
4.
Mocsai A: Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 2013, 210:1283-1299.
5.
Kovacs EJ, Palmer JL, Fortin CF, Fulop T Jr, Goldstein DR, Linton PJ: Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 2009, 30:319-324.
6.
Mahbub S, Brubaker AL, Kovacs EJ: Aging of the innate immune system: an update. Curr Immunol Rev 2011, 7:104-115.
7.
Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC: Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 2009, 30:325-333.
8.
Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ: Aging and innate immune cells. J Leuk Biol 2004, 76:291-299.
9.
Schroder AK, Rink L: Neutrophil immunity of the elderly. Mech Ageing Dev 2003, 124:419-425.
10. Shaw AC, Goldstein DR, Montgomery RR: Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013, 13:875-887. 11. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM: Aging of the innate immune system. Curr Opin Immunol 2010, 22:507-513. 12. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T: Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 2012, 24:331-341. 13. Wessels I, Jansen J, Rink L, Uciechowski P: Immunosenescence of polymorphonuclear neutrophils. TheScientificWorldJournal 2010, 10:145-160. 14. Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley RA, Lord JM: Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 2014, 123:239-248. The authors demonstrated that neutrophils from aged individuals exhibit reduced migratory accuracy in response to various stimuli without an effect on chemokinesis. Increased constitutive PI3K signaling in the neutrophils of aged hosts was responsible for the deficit as migratory accuracy could be corrected by blocking of PI3Kgamma or delta. The broader implication of reduced accuracy of chemotaxis is the potential to induce bystander damage in the tissues of aged hosts. 15. Chen MM, Palmer JL, Plackett TP, Deburghgraeve CR, Kovacs EJ: Age-related differences in the neutrophil response to pulmonary pseudomonas infection. Exp Gerontol 2014. (Epub ahead of print). 16. Brubaker AL, Rendon JL, Ramirez L, Choudhry MA, Kovacs EJ: Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J Immunol 2013, 190:1746-1757. The authors demonstrated that aged mice, compared to young mice, showed decreased neutrophil recruitment to an injection of KC. The reduced chemotaxis was suggested to be the primary defect responsible for the slow clearance of S. aureus and poor wound healing. 17. Tseng CW, Kyme PA, Arruda A, Ramanujan VK, Tawackoli W, Liu GY: Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus. PLOS ONE 2012, 7:4145-4154. This study investigated the role of NETs in defense against S. aureus. NET production was shown to be reduced with aging and was causally associated with increased dissemination of S. aureus to distant organs. 18. Gomez CR, Hirano S, Cutro BT, Birjandi S, Baila H, Nomellini V, Kovacs EJ: Advanced age exacerbates the pulmonary inflammatory response after lipopolysaccharide exposure. Crit Care Med 2007, 35:246-251. 19. Wulfert FM, van Meurs M, Kurniati NF, Jongman RM, Houwertjes MC, Heeringa P, Struys MM, Zijlstra JG, Molema G: Age-dependent role of microvascular endothelial and polymorphonuclear cells in lipopolysaccharide-induced acute kidney injury. Anesthesiology 2012, 117:126-136. In this murine model of LPS induced kidney injury, increased neutrophil recruitment was measured in aged mice, which correlated with increased P-selectin and E-selectin expression in the kidneys. Surprisingly, neutrophil depletion in aged mice worsened kidney pathology. www.sciencedirect.com
20. Nomellini V, Brubaker AL, Mahbub S, Palmer JL, Gomez CR, Kovacs EJ: Dysregulation of neutrophil cxcr2 and pulmonary endothelial icam-1 promotes age-related pulmonary inflammation. Aging Dis 2012, 3:234-247. 21. Brinkmann V, Zychlinsky A: Beneficial suicide: why neutrophils die to make nets. Nat Rev Microbiol 2007, 5:577-582. 22. Qian F, Guo X, Wang X, Yuan X, Chen S, Malawista SF, Bockenstedt LK, Allore HG, Montgomery RR: Reduced bioenergetics and Toll-like Receptor 1 function in human polymorphonuclear leukocytes. Aging 2014, 6:131-139. In this study, neutrophils from elderly humans exhibit defective responses to TLR1 and TLR4 stimulation. This correlated with decreased intracellular glucose accumulation, suggesting that bioenergetics could be an important factor contributing to decreased neutrophil functions in old age. 23. Wartha F, Beiter K, Normark S, Henriques-Normark B: Neutrophil extracellular traps: casting the net over pathogenesis. Curr Opin Microbiol 2007, 10:52-56. 24. Walker MJ, Hollands A, Sanderson-Smith ML, Cole JN, Kirk JK, Henningham A, McArthur JD, Dinkla K, Aziz RK, Kansal RG, Simpson AJ et al.: Dnase sda1 provides selection pressure for a switch to invasive group a streptococcal infection. Nat Med 2007, 13:981-985. 25. Sharma A, Steichen AL, Jondle CN, Mishra BB, Sharma J: Protective role of mincle in bacterial pneumonia by regulation of neutrophil mediated phagocytosis and extracellular trap formation. J Infect Dis 2014. [Epub ahead of print]. 26. Kirchner T, Moller S, Klinger M, Solbach W, Laskay T, Behnen M: The impact of various reactive oxygen species on the formation of neutrophil extracellular traps. Mediators Inflamm 2012:8491-8536. 27. Hakkim A, Fuchs TA, Martinez NE, Hess S, Prinz H, Zychlinsky A, Waldmann H: Activation of the raf-mek-erk pathway is required for neutrophil extracellular trap formation. Nat Chem Biol 2011, 7:75-77. 28. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y: Pad4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010, 207:1853-1862. 29. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A: Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010, 191:677-691. 30. Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, Zbytnuik LD, Pittman K, Asaduzzaman M, Wu K, Meijndert HC, Malawista SE et al.: Infection-induced netosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012, 18:1386-1393. 31. Tsuda Y, Takahashi H, Kobayashi M, Hanafusa T, Herndon DN, Suzuki F: Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillinresistant Staphylococcus aureus. Immunity 2004, 21:215-226. This study documented the existence of at least two distinct neutrophil subsets that produce different cytokines and chemokines, and induce either M1 or M2 macrophages. The subsets were isolated from mice that were susceptible or resistant to MRSA. A third neutrophil subset obtained from naı¨ve mice could be converted to either subsets. 32. Dalboni TM, Abe AE, de Oliveira CE, Lara VS, Campanelli AP, Gasparoto CT, Gasparoto TH: Activation profile of cxcl8stimulated neutrophils and aging. Cytokine 2013, 61:716-719. 33. Scholz JL, Diaz A, Riley RL, Cancro MP, Frasca D: A comparative review of aging and b cell function in mice and humans. Curr Opin Immunol 2013, 25:504-510. 34. Duraisingham SS, Rouphael N, Cavanagh MM, Nakaya HI, Goronzy JJ, Pulendran B: Systems biology of vaccination in the elderly. Curr Top Microbiol Immunol 2012, 363:117-142. 35. Goronzy JJ, Weyand CM: Understanding immunosenescence to improve responses to vaccines. Nat Immunol 2013, 14:428-436. 36. Nomellini V, Faunce DE, Gomez CR, Kovacs EJ: An ageassociated increase in pulmonary inflammation after burn injury is abrogated by cxcr2 inhibition. J Leuk Biol 2008, 83:1493-1501. Current Opinion in Immunology 2014, 29:43–48
48 Immune senescence
This model of burn injury demonstrated that young and aged mice induced similar pulmonary recruitment of neutrophils at an early time point, but neutrophil clearance was impaired in aged mice and that promoted excess inflammation. 37. Soehnlein O, Lindbom L: Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol 2010, 10:427-439. 38. Aprahamian T, Takemura Y, Goukassian D, Walsh K: Ageing is associated with diminished apoptotic cell clearance in vivo. Clin Exp Immunol 2008, 152:448-455. This study demonstrated that aged hosts have impaired clearance of apoptotic keratinocytes and Jurkat T cells. Defective clearance of apoptotic bodies could be demonstrated by pretreatment of macrophages with serum from aged hosts but not serum from young hosts. Inability to clear apoptotic cells could be a cause of increased inflammation in aged hosts. 39. Woodfin A, Voisin MB, Beyrau M, Colom B, Caille D, Diapouli FM, Nash GB, Chavakis T, Albelda SM, Rainger GE, Meda P et al.: The junctional adhesion molecule jam-c regulates polarized transendothelial migration of neutrophils in vivo. Nat Immunol 2011, 12:761-769. 40. Cauwe B, Martens E, Proost P, Opdenakker G: Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase b/mmp-9 substrates. Integr Biol: Quant Biosci Nano Macro 2009, 1:404-426. 41. Lively S, Schlichter LC: Age-related comparisons of evolution of the inflammatory response after intracerebral hemorrhage in rats. Transl Stroke Res 2012, 3(Suppl. 1):132-146. 42. Tillack K, Breiden P, Martin R, Sospedra M: T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J Immunol 2012, 188:31503159. 43. Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A: Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 2010, 107:9813-9818. 44. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ et al.: Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 2011, 3:20-73. 45. Farrera C, Fadeel B: Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol 2013, 191:2647-2656. 46. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S: Innate immunity in aging: impact on macrophage function. Aging Cell 2004, 3:161-167.
Current Opinion in Immunology 2014, 29:43–48
47. Serhan CN: Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? Am J Pathol 2010, 177:1576-1591. 48. Serhan CN, Chiang N, Van Dyke TE: Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008, 8:349-361. 49. Gangemi S, Pescara L, D’Urbano E, Basile G, Nicita-Mauro V, Davi G, Romano M: Aging is characterized by a profound reduction in anti-inflammatory lipoxin a4 levels. Exp Gerontol 2005, 40:612-614. 50. Stout-Delgado HW, Du W, Shirali AC, Booth CJ, Goldstein DR: Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe 2009, 6:446-456. This study demonstrated higher IL-17 production by Natural Killer T cells following HSV infection in aged mice. Increased IL17 promoted neutrophil activation and induced liver necrosis and death of the mice. Liver damage and mortality were prevented by administration of IL-17 blocking antibody or by neutrophil depletion. 51. Fortin CF, McDonald PP, Lesur O, Fulop T Jr: Aging and neutrophils: there is still much to do. Rejuven Res 2008, 11:873-882. 52. Soehnlein O: Multiple roles for neutrophils in atherosclerosis. Circ Res 2012, 110:875-888. 53. Elgazar-Carmon V, Rudich A, Hadad N, Levy R: Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 2008, 49:1894-1903. 54. Talukdar S, Oh da Y, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J et al.: Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012, 18:1407-1412. 55. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM: Polarization of tumor-associated neutrophil phenotype by tgf-beta: ‘‘N1’’ versus ‘‘n2’’ tan. Cancer Cell 2009, 16:183-194. 56. Gabrilovich DI, Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009, 9:162174. 57. Enioutina EY, Bareyan D, Daynes RA: A role for immature myeloid cells in immune senescence. J Immunol 2011, 186:697707. This paper documented the increased presence of immature myeloid cells that bear phenotypic resemblence to MDSCs associated with tumors and chronic inflammatory conditions. The immature myeloid cells produce high levels of proinflammtory cytokines and suppress T cell proliferation through an NO-dependent mechanism. The finding of increased number of these MDSCs in aged mice suggests a link to the higher incidence of cancer and chronic inflammation in aged individuals.
www.sciencedirect.com
ScienceDirect Expanding roles of neutrophils in aging hosts Ching Wen Tseng1,2 and George Y Liu1,2 Neutrophils’ role in the clearance of pathogens is well documented, but there is increasing appreciation that neutrophils can participate in the resolution of infection and inflammation. An obvious implication is that alteration of neutrophil functions with old age could significant impact both susceptibility of the host to infection and inflammatory conditions. Advances in recent years suggest additional chinks in the neutrophil antimicrobial arsenals in aged hosts, which render neutrophils less capable of killing pathogens. Moreover there is evidence that changes in neutrophil cross-talk with other immune cells also contribute to poor resolution of inflammation. These advances provide new insight on how these phagocytic cells could contribute to age-related diseases. Addresses 1 Division of Pediatric Infectious Diseases and the Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States 2 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States Corresponding author: Liu, George Y ([email protected])
Current Opinion in Immunology 2014, 29:43–48 This review comes from a themed issue on Immune senescence Edited by Tamas Fu¨lo¨p and Ruth Montgomery
0952-7915/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coi.2014.03.009
Introduction Neutrophils were once viewed as phagocytic cells packed with antimicrobial substances programmed solely to kill pathogens. After elimination of the microbes from the infection site, they are removed to bring the infection to a resolution. Exciting advances in recent years have altered this simplistic view of neutrophils [1–4]. Added to the phagocytes’ arsenals are neutrophil extracellular DNA traps (NETs) which immobilize bacteria. Neutrophil subsets with either pro-inflammatory or anti-inflammatory properties have been characterized. Additionally, an abundance of data suggests that neutrophils are active players in the orchestration of host defense and resolution of inflammation. These novel findings have provided a more dynamic framework to reevaluate the role of neutrophils in age-related diseases. In this review, we summarize recent developments in the neutrophil and aging field (Figure 1), and discuss their www.sciencedirect.com
significance in the context of the new neutrophil biology and age-related diseases (Table 1). Because of space limitation, the reader is referred to many excellent reviews on the impact of aging on neutrophils [5–13].
Recruitment to the site of inflammation It is well documented that aged individuals are more susceptible to infection. This is unlikely the effect of aging on myelopoiesis since the numbers of circulating neutrophils at baseline and during acute inflammation are not reduced in elderly hosts (reviewed in [13]). Instead, defects in neutrophil recruitment or microbial killing are probably responsible for age-related susceptibility to infection. Neutrophil recruitment is an elaborate process in which circulating neutrophils are attracted to the site of inflammation by following chemokine trails laid out by microbes or host cells [2]. Surface chemokine receptors allow neutrophils to survey chemokine gradients along the vascular endothelium, and subsequent engagement of integrins and CD15 on neutrophils with P-selectin glycoprotein ligand-1 (PSGL-1), and P-selectins, L-selectins and E-selectins, and ICAMs on endothelial cells leads to neutrophil attachment and transmigration. Though defects in neutrophil chemotaxis are well documented in aging hosts, several new studies have provided important insight on how recruitment is compromised with aging. The most interesting report is a study by Sapey and colleagues describing decreased accuracy of neutrophil migration to various inflammatory stimuli without loss of chemokinesis [14]. The authors showed that constitutive activation of phosphoinositide 3-kinase (PI3K) was responsible for the inaccurate migration and inhibition of PI3Kg or d restored accuracy of the directional chemotaxis. In a model of pseudomonas lung infection, inaccurate neutrophil migration was offered as an explanation for the high number of neutrophils stranded in the lung parenchyma of aged mice [15]. By comparison, neutrophils from young mice were primarily recruited to the alveolar space to more effectively combat the infection. Though neutrophil chemotactic deficits are well described in vitro in aged hosts (reviewed in [13]), several reports in the past years have underlined the complexity of neutrophil recruitment in vivo. Three infection studies performed using Staphylococcus aureus or P. aeruginosa reported reduced neutrophil numbers at the infection site [15,16,17]. Impaired neutrophil recruitment could not be explained by local chemokine release as chemokines were found to be more elevated in aged mice in two of the studies [15,16]. Additionally, elevated chemokine Current Opinion in Immunology 2014, 29:43–48
44 Immune senescence
Figure 1
Microbial killing ↓ Phagocytosis ↓ ROS ↓ NETs ↓
Clearance of PMNs, NETs, and DAMPs ? Pro-resolvins and resolvins ?
NETs Apoptotic PMNs
Microbes
Chronic Inflammation ↑
Resolution ↓
Mφ
Endothelial cells
PMNs
↓
Chemotaxis in vitro ↓ in vivo ↓
Bloodstream
Current Opinion in Immunology
PMN functions and senescence. Arrows indicate changes with aging.
receptor (CXCR2) expression on circulating neutrophils did not improve recruitment of the neutrophils in one study [16]. The findings led the authors to suggest that intrinsic defect in CXCR2 signaling likely accounted for the recruitment defect. In contrast to the infectious
stimuli, LPS injection or thermal injury induced higher neutrophil accumulation in aged mice compared to young mice [18,19,20]. Increased expressions of ICAM-1 on lung endothelial cells or E-selectins and P-selectins in the kidneys correlated with neutrophil accumulation and
Table 1 Changes of neutrophil-related functionsin aged hosts
Neutrophil number Neutrophil chemotaxis In vitro In vivo Neutrophil antimicrobial functions Phagocytosis ROS Elastase NETs Clearance of dead neutrophils Clearance of DAMPs or NETs Pro-resolvins, resolvins, or protectins Cytokines Pro-inflammatory Anti-inflammatory Existence of neutrophil types/subsets Pro-inflammatory/promoting tissue injury Anti-inflammatory/protective against tissue injury
Current Opinion in Immunology 2014, 29:43–48
Changes
Comments
$
[12,13]
# #, , or "
[13,14] [15,16,17,18,19,20,36]
# # or $ Variable # Unknown Unknown Unknown
[13] [13] Stimulus dependent [32] [17] # clearance of apoptotickeratinocytes and T cells with aging [38]
# or $ "
Stimulus dependent [17,22,32] [32]
[14,36,50] [19]
Pro-inflammatory MDSCs "with aging [57]
# urinary LXA4 with aging [49]
www.sciencedirect.com
Neutrophils and aging Tseng and Liu 45
were suggested to induce increased neutrophil adhesion [18,20]. However, it remains unclear why infectious and noninfectious stimuli induced different recruitment of neutrophils in young and aged hosts.
Antimicrobial responses Neutrophils from aged host exhibit impaired clearance of pathogens, in addition to chemotactic defects [13]. Normal neutrophil antimicrobial activities include the elaboration of reactive oxygen species (ROS) and antimicrobial proteinases, phagocytosis of invading organisms, and release of NETs [1–3,21]. Many reports suggest that phagocytosis and ROS production are compromised in aged hosts (reviewed in [13]). The underlying mechanisms are not fully understood, but a recent study found reduced glucose accumulation in neutrophils derived from aged individuals in response to TLR1 or TLR4 stimulation. Deficiency in bioenergetics could therefore provide an important explanation for the overall decreased functions of neutrophils with aging [22]. NETs represent a recently described antimicrobial mechanism that is triggered by a variety of pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs) [23]. NETs are chromatin mesh actively expelled by neutrophils as a way to trap pathogens. They promote killing of microbes by bringing the pathogens in close proximity to bound antimicrobial substances and by extending contact between pathogens and antimicrobial proteins. Trapped bacteria are thereby prevented from dissemination into the bloodstream [24]. The mechanism driving NET formation is not completely understood, but C-type lectin receptor mincle, the Raf-MEK-ERK pathway, and NADPH oxidase appear to be important [25– 27]. Deamination of histone by PAD4 drives the disassembly of chromatin, and myeloperoxidase and neutrophil elastase further contribute to the decondensation of chromatin [28,29]. Interestingly, even after extrusion of the NETs, neutrophils can engage in purposeful pursuit and clearance of pathogens [30]. Neutrophils from aged mice produce fewer NETs in response to S. aureus or PMA stimulation [17]. In vivo, fewer NETs are visualized at the site of S. aureus skin infection in aged mice compared to young mice [17], and this partly contributed to increased dissemination of S. aureus into the bloodstream and distant organs. The mechanisms responsible for decreased NET formation in aged hosts are not known, but given the well documented decreased NADPH activity in aged hosts and their involvement in NET formation [26], decreased ROS likely contribute to this age-related change.
Cross-talk with other immune cells Neutrophils perform a variety of functions that complement their antimicrobial activities. They secrete chemokines and cytokines, recruit monocytes, neutrophils, www.sciencedirect.com
and dendritic cells, express MHC class II and costimulatory molecules on their cell surface, induce maturation of DCs, and transport antigens to lymph nodes to support priming of T cells [1]. Increasing evidence suggests that distinct neutrophil subsets exist. In one study, Tsuda and colleagues demonstrated three neutrophil subset phenotypes [31]: PMNs isolated from MRSA-resistant mice that express IL-12 and CCL3 and induce M1 macrophages, PMNs isolated from MRSA-sensitive mice that express IL-10 and CCL2 and activate M2 macrophages, and a third type of PMNs isolated from naı¨ve mice that could convert to either type of neutrophils. The recruitment of the various subsets of neutrophils was therefore suggested to have an influence on the clearance of pathogens. Although neutrophil subsets have not been investigated in aged hosts, recent reports indicated that neutrophils from aged hosts secrete lower levels of chemokines (MIP-2, KC, IL8) and pro-inflammatory cytokine IL6 in response to various stimuli [17,22,32]. Conversely, they produce higher level of IL-10 in response to LPS [32] and show no differences for many of the other cytokines and stimuli surveyed. Cross-talk between neutrophils and other immune cells will be an important area of studies as it promises to shed light on why aged individuals have increased susceptibility to infection and slow resolution and why they exhibit poor adaptive immune response to pathogens and vaccine antigens [33–35].
Resolution versus chronic inflammation Following clearance of pathogens, the next major tasks of the immune system are to remove dead neutrophils, clean off debris, shut down inflammation, and begin the process of healing. Aged individuals exhibit slow healing and have a predilection for chronic inflammatory conditions. Therefore, resolution of inflammation is likely compromised during aging. Arguably, the most important prerequisite to resolution is the clearance of neutrophils. In a burn model, young and aged mice showed similar neutrophil recruitment at an early time point, but the neutrophils persisted longer in aged mice [36], suggesting slower clearance of the phagocytic cells in aged animals. Clearance of apoptotic neutrophils is usually accomplished by macrophages that recognize ‘eat me’ signals displayed on dead neutrophils. Engulfment of apoptotic cells, in turn, induces macrophage to assume an anti-inflammatory phenotype necessary for the resolution of inflammation [37]. Macrophagemediated clearance of apoptotic Jurkat cells and keratinocytes has been shown to be compromised in aged mice based on one study. In that study, the rate of apoptotic cell clearance was dependent on factors present in the serum of aged mice rather than macrophage-intrinsic factors [38]. The study did not specifically address clearance of neutrophils. Clearance of live neutrophils can be enacted by the neutrophils themselves. Recently, studies Current Opinion in Immunology 2014, 29:43–48
46 Immune senescence
in mice and humans have demonstrated that neutrophils can undergo reverse migration, a mechanism that is dependent on downregulation of junctional adhesion molecule JAM-C [39]. Reverse migration could alleviate inflammation from the infection site but has the potential to disseminate inflammation systemically.
suggesting the presence of protective neutrophils [19]. It should be evident that resolution of inflammation is complex and involves close coordination between neutrophils and other immune cells. Further exploration of these mechanisms could provide critical clues on how neutrophils contribute to chronic inflammation.
In addition to PAMPs that are found in abundance during infection, danger-associated molecular patterns (DAMPs) are produced by the host and further amplify the proinflammatory signals. Removal of PAMPs and DAMPs are required to resolve inflammation. Neutrophils express certain proteases, such as matrix metallopeptidase-9 (MMP9), which degrade DAMPS (high-mobility group protein B1 (HMGB1) and heat-shock proteins), preventing their release from damaged cells [40]. Neutrophil MMP9 expression has not been studied in aged subjects, however in response to intracerebral hemorrhage, aged rats exhibit delayed and decreased MMP9 expression from myeloid cells [41]. NETs represent another highly pro-inflammatory substance that must be cleared after infection. They facilitate priming of T cells and have been linked to the induction of autoimmune diseases like Lupus [42–44]. Though they do not induce cytokines on their own, NETs amplify the pro-inflammatory property of LPS [45]. Macrophages derived from human monocytes as well as complement C1q from human sera have been shown to facilitate removal of NETs [45]. NET clearance in old age has not been investigated, though it is clear that macrophages from aged mice show impaired phagocytosis [46].
Perspectives
During the course of infection or inflammation, neutrophils undergo important changes in their lipid profile, turning down pro-inflammatory lipids while up-regulating expression of pro-resolvins, resolvins, and protectins [47,48]. As their names suggest, pro-resolvins, resolvins, and protectins are important molecules that orchestrate the resolution of inflammation or infection. Lipoxin A4 (LXA4), an important pro-resolvin, inhibits FPR1-dependent migration, promotes recruitment of monocytes, and induces phagocytosis of apoptotic neutrophils by macrophages [47,48]. A defect in pro-resolvin or resolvin secretion would explain the proinflammatory predilection of aged hosts. Pertinently, a study of aged individuals demonstrated a decreased urinary level of LXA4 levels [49].
In summary, neutrophils have undergone an image makeover. They have expanded their involvement in all facets of innate and adaptive immunity and in a variety of human diseases. These discoveries should prompt a reevaluation of neutrophil contribution to aging-related diseases.
The outcome of inflammation could also be influenced by the type of neutrophils recruited to fight the infection, as described above. In a systemic Herpes simplex virus infection model, Stout-Delgado and colleagues demonstrated that IL-17 is produced in excess in aged mice leading to accumulation of overactive neutrophils in the liver [50]. Depletion of the neutrophils or neutralization of IL-17 reduced mortality in the aged mice. By contrast, removal of neutrophils in an LPS induced kidney inflammation model led to worsening organ pathology, Current Opinion in Immunology 2014, 29:43–48
Few years ago, Fortin and colleagues reviewed the potential contribution of neutrophils to a number of age-related diseases and lamented on how little has been done in this important field of research [51]. There are now even more compelling reasons to study neutrophils in relation to aging-related diseases. In atherosclerosis, for example, various neutrophil factors have been shown to contribute to the pathology associated with the different phases of atherosclerotic disease [52]. For diabetes, neutrophil elastase has been directly implicated in the mechanism of insulin resistance [53,54]. Perhaps most interestingly are evidence in cancer of two neutrophil-related or myeloid-related cell subsets that have either pro or anti-tumor function [55,56]. The myeloid cell subsets, termed myeloid derived suppressor cells (MDSCs), are a heterogeneous myeloid progenitor population that could be isolated during infection, inflammatory conditions, or cancer. They play an important role in suppression of T cells and in tumor progression [56]. Importantly, one report showed that pro-inflammatory MDSCs are significantly increased with old age [57], and their increased number correlates with the increased incidence of cancer with old age.
Acknowledgements We apologize that we were unable to cite all relevant studies because of space limitation. GYL received grant support from the Telemedicine and Advanced Technology Research Center (TATRC) at the U.S. Army Medical Research and Materiel Command (USAMRMC) under Award No. W81XWH-09-1-0644.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1.
Mayadas TN, Cullere X, Lowell CA: The multifaceted functions of neutrophils. Annu Rev Pathol 2014, 9:181-218.
2.
Kolaczkowska E, Kubes P: Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013, 13:159-175.
3.
Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A: Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012, 30:459-489. www.sciencedirect.com
Neutrophils and aging Tseng and Liu 47
4.
Mocsai A: Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J Exp Med 2013, 210:1283-1299.
5.
Kovacs EJ, Palmer JL, Fortin CF, Fulop T Jr, Goldstein DR, Linton PJ: Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 2009, 30:319-324.
6.
Mahbub S, Brubaker AL, Kovacs EJ: Aging of the innate immune system: an update. Curr Immunol Rev 2011, 7:104-115.
7.
Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC: Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 2009, 30:325-333.
8.
Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ: Aging and innate immune cells. J Leuk Biol 2004, 76:291-299.
9.
Schroder AK, Rink L: Neutrophil immunity of the elderly. Mech Ageing Dev 2003, 124:419-425.
10. Shaw AC, Goldstein DR, Montgomery RR: Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013, 13:875-887. 11. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM: Aging of the innate immune system. Curr Opin Immunol 2010, 22:507-513. 12. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T: Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 2012, 24:331-341. 13. Wessels I, Jansen J, Rink L, Uciechowski P: Immunosenescence of polymorphonuclear neutrophils. TheScientificWorldJournal 2010, 10:145-160. 14. Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, Insall RH, Stockley RA, Lord JM: Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 2014, 123:239-248. The authors demonstrated that neutrophils from aged individuals exhibit reduced migratory accuracy in response to various stimuli without an effect on chemokinesis. Increased constitutive PI3K signaling in the neutrophils of aged hosts was responsible for the deficit as migratory accuracy could be corrected by blocking of PI3Kgamma or delta. The broader implication of reduced accuracy of chemotaxis is the potential to induce bystander damage in the tissues of aged hosts. 15. Chen MM, Palmer JL, Plackett TP, Deburghgraeve CR, Kovacs EJ: Age-related differences in the neutrophil response to pulmonary pseudomonas infection. Exp Gerontol 2014. (Epub ahead of print). 16. Brubaker AL, Rendon JL, Ramirez L, Choudhry MA, Kovacs EJ: Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J Immunol 2013, 190:1746-1757. The authors demonstrated that aged mice, compared to young mice, showed decreased neutrophil recruitment to an injection of KC. The reduced chemotaxis was suggested to be the primary defect responsible for the slow clearance of S. aureus and poor wound healing. 17. Tseng CW, Kyme PA, Arruda A, Ramanujan VK, Tawackoli W, Liu GY: Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus. PLOS ONE 2012, 7:4145-4154. This study investigated the role of NETs in defense against S. aureus. NET production was shown to be reduced with aging and was causally associated with increased dissemination of S. aureus to distant organs. 18. Gomez CR, Hirano S, Cutro BT, Birjandi S, Baila H, Nomellini V, Kovacs EJ: Advanced age exacerbates the pulmonary inflammatory response after lipopolysaccharide exposure. Crit Care Med 2007, 35:246-251. 19. Wulfert FM, van Meurs M, Kurniati NF, Jongman RM, Houwertjes MC, Heeringa P, Struys MM, Zijlstra JG, Molema G: Age-dependent role of microvascular endothelial and polymorphonuclear cells in lipopolysaccharide-induced acute kidney injury. Anesthesiology 2012, 117:126-136. In this murine model of LPS induced kidney injury, increased neutrophil recruitment was measured in aged mice, which correlated with increased P-selectin and E-selectin expression in the kidneys. Surprisingly, neutrophil depletion in aged mice worsened kidney pathology. www.sciencedirect.com
20. Nomellini V, Brubaker AL, Mahbub S, Palmer JL, Gomez CR, Kovacs EJ: Dysregulation of neutrophil cxcr2 and pulmonary endothelial icam-1 promotes age-related pulmonary inflammation. Aging Dis 2012, 3:234-247. 21. Brinkmann V, Zychlinsky A: Beneficial suicide: why neutrophils die to make nets. Nat Rev Microbiol 2007, 5:577-582. 22. Qian F, Guo X, Wang X, Yuan X, Chen S, Malawista SF, Bockenstedt LK, Allore HG, Montgomery RR: Reduced bioenergetics and Toll-like Receptor 1 function in human polymorphonuclear leukocytes. Aging 2014, 6:131-139. In this study, neutrophils from elderly humans exhibit defective responses to TLR1 and TLR4 stimulation. This correlated with decreased intracellular glucose accumulation, suggesting that bioenergetics could be an important factor contributing to decreased neutrophil functions in old age. 23. Wartha F, Beiter K, Normark S, Henriques-Normark B: Neutrophil extracellular traps: casting the net over pathogenesis. Curr Opin Microbiol 2007, 10:52-56. 24. Walker MJ, Hollands A, Sanderson-Smith ML, Cole JN, Kirk JK, Henningham A, McArthur JD, Dinkla K, Aziz RK, Kansal RG, Simpson AJ et al.: Dnase sda1 provides selection pressure for a switch to invasive group a streptococcal infection. Nat Med 2007, 13:981-985. 25. Sharma A, Steichen AL, Jondle CN, Mishra BB, Sharma J: Protective role of mincle in bacterial pneumonia by regulation of neutrophil mediated phagocytosis and extracellular trap formation. J Infect Dis 2014. [Epub ahead of print]. 26. Kirchner T, Moller S, Klinger M, Solbach W, Laskay T, Behnen M: The impact of various reactive oxygen species on the formation of neutrophil extracellular traps. Mediators Inflamm 2012:8491-8536. 27. Hakkim A, Fuchs TA, Martinez NE, Hess S, Prinz H, Zychlinsky A, Waldmann H: Activation of the raf-mek-erk pathway is required for neutrophil extracellular trap formation. Nat Chem Biol 2011, 7:75-77. 28. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y: Pad4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 2010, 207:1853-1862. 29. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A: Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010, 191:677-691. 30. Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, Zbytnuik LD, Pittman K, Asaduzzaman M, Wu K, Meijndert HC, Malawista SE et al.: Infection-induced netosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012, 18:1386-1393. 31. Tsuda Y, Takahashi H, Kobayashi M, Hanafusa T, Herndon DN, Suzuki F: Three different neutrophil subsets exhibited in mice with different susceptibilities to infection by methicillinresistant Staphylococcus aureus. Immunity 2004, 21:215-226. This study documented the existence of at least two distinct neutrophil subsets that produce different cytokines and chemokines, and induce either M1 or M2 macrophages. The subsets were isolated from mice that were susceptible or resistant to MRSA. A third neutrophil subset obtained from naı¨ve mice could be converted to either subsets. 32. Dalboni TM, Abe AE, de Oliveira CE, Lara VS, Campanelli AP, Gasparoto CT, Gasparoto TH: Activation profile of cxcl8stimulated neutrophils and aging. Cytokine 2013, 61:716-719. 33. Scholz JL, Diaz A, Riley RL, Cancro MP, Frasca D: A comparative review of aging and b cell function in mice and humans. Curr Opin Immunol 2013, 25:504-510. 34. Duraisingham SS, Rouphael N, Cavanagh MM, Nakaya HI, Goronzy JJ, Pulendran B: Systems biology of vaccination in the elderly. Curr Top Microbiol Immunol 2012, 363:117-142. 35. Goronzy JJ, Weyand CM: Understanding immunosenescence to improve responses to vaccines. Nat Immunol 2013, 14:428-436. 36. Nomellini V, Faunce DE, Gomez CR, Kovacs EJ: An ageassociated increase in pulmonary inflammation after burn injury is abrogated by cxcr2 inhibition. J Leuk Biol 2008, 83:1493-1501. Current Opinion in Immunology 2014, 29:43–48
48 Immune senescence
This model of burn injury demonstrated that young and aged mice induced similar pulmonary recruitment of neutrophils at an early time point, but neutrophil clearance was impaired in aged mice and that promoted excess inflammation. 37. Soehnlein O, Lindbom L: Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol 2010, 10:427-439. 38. Aprahamian T, Takemura Y, Goukassian D, Walsh K: Ageing is associated with diminished apoptotic cell clearance in vivo. Clin Exp Immunol 2008, 152:448-455. This study demonstrated that aged hosts have impaired clearance of apoptotic keratinocytes and Jurkat T cells. Defective clearance of apoptotic bodies could be demonstrated by pretreatment of macrophages with serum from aged hosts but not serum from young hosts. Inability to clear apoptotic cells could be a cause of increased inflammation in aged hosts. 39. Woodfin A, Voisin MB, Beyrau M, Colom B, Caille D, Diapouli FM, Nash GB, Chavakis T, Albelda SM, Rainger GE, Meda P et al.: The junctional adhesion molecule jam-c regulates polarized transendothelial migration of neutrophils in vivo. Nat Immunol 2011, 12:761-769. 40. Cauwe B, Martens E, Proost P, Opdenakker G: Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase b/mmp-9 substrates. Integr Biol: Quant Biosci Nano Macro 2009, 1:404-426. 41. Lively S, Schlichter LC: Age-related comparisons of evolution of the inflammatory response after intracerebral hemorrhage in rats. Transl Stroke Res 2012, 3(Suppl. 1):132-146. 42. Tillack K, Breiden P, Martin R, Sospedra M: T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J Immunol 2012, 188:31503159. 43. Hakkim A, Furnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A: Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 2010, 107:9813-9818. 44. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ et al.: Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 2011, 3:20-73. 45. Farrera C, Fadeel B: Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol 2013, 191:2647-2656. 46. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S: Innate immunity in aging: impact on macrophage function. Aging Cell 2004, 3:161-167.
Current Opinion in Immunology 2014, 29:43–48
47. Serhan CN: Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not? Am J Pathol 2010, 177:1576-1591. 48. Serhan CN, Chiang N, Van Dyke TE: Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 2008, 8:349-361. 49. Gangemi S, Pescara L, D’Urbano E, Basile G, Nicita-Mauro V, Davi G, Romano M: Aging is characterized by a profound reduction in anti-inflammatory lipoxin a4 levels. Exp Gerontol 2005, 40:612-614. 50. Stout-Delgado HW, Du W, Shirali AC, Booth CJ, Goldstein DR: Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe 2009, 6:446-456. This study demonstrated higher IL-17 production by Natural Killer T cells following HSV infection in aged mice. Increased IL17 promoted neutrophil activation and induced liver necrosis and death of the mice. Liver damage and mortality were prevented by administration of IL-17 blocking antibody or by neutrophil depletion. 51. Fortin CF, McDonald PP, Lesur O, Fulop T Jr: Aging and neutrophils: there is still much to do. Rejuven Res 2008, 11:873-882. 52. Soehnlein O: Multiple roles for neutrophils in atherosclerosis. Circ Res 2012, 110:875-888. 53. Elgazar-Carmon V, Rudich A, Hadad N, Levy R: Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 2008, 49:1894-1903. 54. Talukdar S, Oh da Y, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J et al.: Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012, 18:1407-1412. 55. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM: Polarization of tumor-associated neutrophil phenotype by tgf-beta: ‘‘N1’’ versus ‘‘n2’’ tan. Cancer Cell 2009, 16:183-194. 56. Gabrilovich DI, Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009, 9:162174. 57. Enioutina EY, Bareyan D, Daynes RA: A role for immature myeloid cells in immune senescence. J Immunol 2011, 186:697707. This paper documented the increased presence of immature myeloid cells that bear phenotypic resemblence to MDSCs associated with tumors and chronic inflammatory conditions. The immature myeloid cells produce high levels of proinflammtory cytokines and suppress T cell proliferation through an NO-dependent mechanism. The finding of increased number of these MDSCs in aged mice suggests a link to the higher incidence of cancer and chronic inflammation in aged individuals.
www.sciencedirect.com
