News and Commentaries 100
γ T cells
A’
αβ small molecule olecu Ags gs
CD1d
peptide Ags recognize MHC and MHC-like
MAIT
A’
α F’
β
Type I NKT TCR
CD1d
NKT lipid Ags
γ δ TCR
F’
δ
γδ
β A’ α
Type II NKT TCR
F’ CD1d
Figure 1 Antigen recognition spectrum of T cells. (a) ab T cells have been shown to recognize a range of diverse antigens, such as peptides, lipids and small metabolites, but only when bound to an antigen-presenting molecule. This population includes classical peptide-reactive T cells, lipid-reactive NKT cells and metabolite-reactive Mucosal associated invariant T (MAIT) cells. gd T cells, in contrast, can recognize antigen-presenting molecules in the absence or presence of antigen. (b) Schematic representation of the modes of binding of ab and gd TCRs to CD1d molecules. CD1d is shown in gray with the two main pockets, A0 and F0, composing the binding groove. The two chains forming the TCR are shown as ellipsoids together with a line connecting the center of masses of each V domain. Note how the Vd1 gd TCR (top) binds on the opposite side of CD1d compared with the type I NKT TCR (middle), but similar to the binding of a mouse type II NKT TCR to mouse CD1d (bottom).
with iNKT-cell activation and their overlapping cytokine spectrum may hint to a functional synergy.
ACKNOWLEDGEMENTS This work was supported by NIH grants AI074952 and AI107318.
1 Uldrich AP, Le Nours J, Pellicci DG, Gherardin NA, McPherson KG, Lim RT et al. CD1d-lipid antigen recognition by the gd TCR. Nature Immunol 2013; 14: 1137–1145. 2 Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25: 297–336. 3 Vantourout P, Hayday A. Six-of-the-best: unique contributions of gd T cells to immunology. Nat Rev Immunol 2013; 13: 88–100. 4 Mangan BA, Dunne MR, O’Reilly VP, Dunne PJ, Exley MA, O’Shea D et al. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vd3 T cells. J Immunol 2013; 191: 30–34. 5 Adams EJ, Chien YH, Garcia KC. Structure of a gd T cell receptor in complex with the nonclassical MHC T22. Science 2005; 308: 227–231. 6 Vavassori S, Kumar A, Wan GS, Ramanjaneyulu GS, Cavallari M, El Daker S et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gammadelta T cells. Nature Immunol 2013; 14: 908–916. 7 Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 2007; 448: 44–49. 8 Girardi E, Maricic I, Wang J, Mac TT, Iyer P, Kumar V et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nature Immunol 2012; 13: 851–856. 9 Patel O, Pellicci DG, Gras S, Sandoval-Romero ML, Uldrich AP, Mallevaey T et al. Recognition of CD1dsulfatide mediated by a type II natural killer T cell antigen receptor. Nature Immunol 2012; 13: 857–863.
Antiviral responses in adipocytes
Viruses ‘chew the fat’!? Paul Hertzog Immunology and Cell Biology (2014) 92, 100–102; doi:10.1038/icb.2013.91; published online 14 January 2014
T
he innate immune response represents a broad aspect of the host response to environmental stress and homeostatic cues. The stress can take the form of infection, so-called ‘sterile’ inflammatory stimuli (for example, metabolic bi-products such as uric acid and cholesterol) and tumor cells. Examples of homeostatic stimuli include commensal micro-organisms, nutrients and components of extracellular matrix. These stimuli are sensed by a series of so-called pattern recognition receptors (PRRs) that include the Toll like receptors (TLRs), RIGI like helicases (RLHs), NOD-like receptors (NLRs) and emerging family of intracellular DNA sensors (for example, DDX, DHX, Aim2, cGAS, STING) and C-type Lectins.1,2 The innate immune response drives pathways Professor P Hertzog is at Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Victoria 3168, Australia E-mail: [email protected]
Immunology and Cell Biology
that activate antiviral and antibacterial pathways, and sculpt the adaptive immune response via the production of chemokines and cytokines, including tumor necrosis factor (TNF)-a, interleukin-6 (IL6), IL-1b and type I interferons (IFNs). An effective innate response results in resolution of infection, return to homeostasis and priming of an adaptive response or memory should it be required. An uncontrolled innate immune response can lead to acute toxicity and chronic diseases, including autoimmune disease, cancer, and chronic infectious/ inflammatory diseases and other sequelae. There has been considerable interest of late in the intersection of innate immune responses, inflammation and metabolism. Metabolic products such as uric acid and cholesterol can activate NLRP3 inflammasome responses.3,4 Innate pathways contribute to metabolic diseases such as diabetes5 and atherosclerosis.4 Furthermore,
the Gram-negative bacterial cell wall component, lipopolysaccharide (LPS), induces a switch in the metabolic state of macrophages from oxidative phosphorylation to glycolysis, which impacts on the production of the proinflammatory cytokine, IL-1b via succinate production.6 Most of these studies have concentrated on immune cells, principally macrophages, dendrite cell and T cells whose metabolic state is also critical to their immune function.7 The study herein by Yu et al.8 reports that not only immune cells, but also adipocytes, which are important cells in the body’s metabolic state, and their precursor cells express antiviral PRRs such as TLR3, MDA5 and RIG- I, which can respond to cognate ligands by producing IL6, TNFa and type I IFNs. However, stimulation of pre-adipocytes, while generating a strong immune response, inhibits their differentiation into mature adipocytes and decreases the production of
News and Commentaries 101
Virus
PRRs
IL-6, TNFα
PRRs
IFNs α/β Antiviral ISGs
Antiviral ISGs
Pre adipocyte
Adipocyte
Adipokines (leptin, etc.)
Immune response
Metabolism
Figure 1 Viral sensing by adipocytes. Pattern recognition receptors (PRRs) are expressed in adipocytes and pre-adipocytes, and can induce the proinflammatory cytokines TNFa, IL6 and IFNs a/b upon virus recognition. IFNs a/b likely then feed back to induce antiviral ISG expression within these cell types. Additionally, PRR engagement suppresses both pre-adipocyte differentiation into adipocytes and the production of adipokines, thereby influencing both metabolism and the immune response.
adipokines such as leptin, adiponectin and resistin, which are known to modulate immune functions and metabolism. The context of this study is important because reciprocal associations between viral infection and obesity have been implied in the past (infection affecting weight gain or obesity predisposing to infection).9 In this study, Yu et al. demonstrated high expression of the viral-sensing PRRs, TLR3, MDA5 and RIG-I in adipose tissue, whereas TLR7 and 9 had low expression. It would be interesting to also measure the rapidly growing list of intracellular viral DNA sensors2 to ascertain the full potential of these cells’ ability to respond to components of different viruses. Both transfected (activating RLH’s) and extracellular poly I:C (activating TLR3)
activated NF-kB and IRF3 pathways and production of proinflammatory cytokines TNFa, IL6 and type I IFNs via the aforementioned receptors. Furthermore, IFN-induced antiviral genes such as ISG15, 20 50 OAS1 and Mx were also induced by poly I:C, presumably via secondary signaling through IFN receptors, although this was not determined. The authors measured responses by assessing both transcripts and protein levels and used cells from knockout mice or those with PRRs knocked down by RNA interference to prove the modes of action. These results demonstrate that these cells could be an important, perhaps overlooked, contributor to the body’s innate immune response to viral infection—particular given
the significant proportion of these cells in the body (and even more so in obese people). It builds on a body of work showing adipocytes express TLRs 2 and 4 and can response to bacterial ligands with a classical innate immune response.10 While the expression of PRRs and the magnitude of the responses were substantial in both pre-adipocytes and mature adipocytes (the former were, in fact, more robust), the activation of PRRs inhibited the differentiation of precursor cells and their production of adipokines. There is considerable literature on the immunoregulatory roles of adipokines;11 so the impact of activation of adipocyte PRRs in a viral infection could be not only an anticipated significant contribution to the innate immune response Immunology and Cell Biology
News and Commentaries 102
(via classic immunoregulatory cytokines plus adipokines), but also an impact on metabolic state via adipokines (Figure 1). One can speculate on the broad significance of these findings. The reported changes could represent an evolutionarily conserved part of the host response; that is, to dampen metabolism and conserve energy to fight infection, not only by effects on the metabolic state of immune cells as previously reported, but also on parenchymal cells of adipose tissue, whose generation is even impaired. However, this would appear to be at odds with reports that viruses increase adiposity in animal models.9,11 This discrepancy remains to be resolved. Future studies should address several issues including assessment of the response to relevant viral infection, not just isolated products. Other ‘antiviral’ PRRs should also be assessed. It would be interesting to know
the mechanism (which PRR pathway and components) of inhibition of pre-adipocyte differentiation and suppression of adipokines production. Furthermore, it remains to be demonstrated whether these effects observed in vitro translate to the whole animal and from the mouse model to humans.
1 Goutagny N, Fitzgerald KA. Pattern recognition receptors: an update. Expert Rev Clin Immunol 2006; 2: 569–583. 2 Keating SE, Baran M, Bowie AG. Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol 2011; 32: 574–581. 3 Rock KL, Kataoka H, Lai JJ. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 2013; 9: 13–23. 4 Duewell P, Kono H, Rayner KJ, Sirois CM Vladimer G, Bauernfeind FG et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357–1361.
5 Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1b in type 2 diabetes. Nat Immunol 2010; 11: 897–904. 6 Tannahill GM, Curtis AM, Adamik J, PalssonMcDermott EM, McGettrick AF, Goel G et al. Succinate is an inflammatory signal that induces IL-1b through HIF-1a. Nature 2013; 496: 238–242. 7 McGettrick AF, O’Neill LA. How metabolism generates signals during innate immunity and inflammation. J Biol Chem 2013; 288: 22893–22898. 8 Yu L, Yan K, Liu P, Li N, Liu Z, Zhu W et al. Pattern recognition receptor-initiated innate antiviral response in mouse adipose cells. Immunol Cell Biol 2014; 92: 105–115. 9 Hegde V, Dhurandhar NV. Microbes and obesity— interrelationship between infection, adipose tissue and the immune system. Clin Microbiol Infect 2013; 19: 314–320. 10 Schaffler A, Scholmerich J, Slazberger B. Adipose tissue as an immunological organ: Toll Like receptors, C1q/TNFs and CTRPs. Trends Immunol 2007; 28: 393–399. 11 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–783.
GADD34 in granulocyte production
Linking stress granulopoiesis to protein synthesis through GADD34 Hrishikesh M Mehta and Seth J Corey Immunology and Cell Biology (2014) 92, 102–104; doi:10.1038/icb.2013.107; published online 14 January 2014
n the current issue, Nishio et al.1 propose a novel role for the growth arrest and DNA damage inducible 34 (GADD34) in the suppression of myelopoiesis and stress granulopoiesis. They observed that older Gadd34 / mice displayed an increase in both immature (Gr1low CD11b þ ) and mature granulocytes (Gr1hi CD11b þ ). This age-dependent expansion was also observed in hematopoietic stem cells (HSCs) and early myeloid progenitors. They showed that GADD34 expression was highest in HSCs, which suggests that GADD34 mediates its inhibition of myelopoiesis at a stem cell stage. The authors attributed the expansion observed in the Gadd34 / mice to an age-related increase in the gut microbiome, which triggers production of granulocyte colony-stimulating factor (GCSF), the most
I
Dr HM Mehta and Professor SJ Corey are at Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA E-mail: [email protected]
Immunology and Cell Biology
important growth factor for production of granulocytes. Further, they provide a mechanism for GADD34-mediated suppression of GCSF Receptor signaling, through inhibition of activation of Lyn and STAT3, two important signaling molecules for GCSF Receptor-mediated proliferation and differentiation of myeloid progenitors (Figure 1).2,3 While GADD34 expression was first identified through a screen for genes expressed following genotoxic injury due to irradiation or alkylating agents,4 subsequent studies suggest its primary role in the unfolded protein response (UPR). Upregulation of GADD34 occurs during UPR, an evolutionarily conserved pathway to protect cells. Unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen, which triggers a chain reaction of biochemical events to limit cell injury. Prolonged activation of UPR leads, however, to apoptosis. An important sensor of the
UPR is the double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) (Figure 1). PERK activation involves dissociation of B-cell immunoglobulin heavy chain-binding protein (BiP), a molecular chaperone that binds to unfolded proteins in the ER. Dissociation of BiP drives oligomerization of PERK, resulting in the trans-autophosphorylation of PERK. Phosphorylated PERK then phosphorylates elongation initiation factor 2a (eIF2a), which downregulates protein expression. Although eIF2a expression shuts off translation of most mRNAs, it enhances the translation of activating transcription factor 4 (ATF-4) mRNA, which under non-stressed conditions is not translated to the ATF-4 protein.5 ATF-4 then drives expression of C/EBP homologous protein (CHOP) and GADD34. CHOP also induces GADD34, further increasing its expression.6 GADD34 serves as an inducible regulatory subunit of the PP1 holoenzyme and
γ T cells
A’
αβ small molecule olecu Ags gs
CD1d
peptide Ags recognize MHC and MHC-like
MAIT
A’
α F’
β
Type I NKT TCR
CD1d
NKT lipid Ags
γ δ TCR
F’
δ
γδ
β A’ α
Type II NKT TCR
F’ CD1d
Figure 1 Antigen recognition spectrum of T cells. (a) ab T cells have been shown to recognize a range of diverse antigens, such as peptides, lipids and small metabolites, but only when bound to an antigen-presenting molecule. This population includes classical peptide-reactive T cells, lipid-reactive NKT cells and metabolite-reactive Mucosal associated invariant T (MAIT) cells. gd T cells, in contrast, can recognize antigen-presenting molecules in the absence or presence of antigen. (b) Schematic representation of the modes of binding of ab and gd TCRs to CD1d molecules. CD1d is shown in gray with the two main pockets, A0 and F0, composing the binding groove. The two chains forming the TCR are shown as ellipsoids together with a line connecting the center of masses of each V domain. Note how the Vd1 gd TCR (top) binds on the opposite side of CD1d compared with the type I NKT TCR (middle), but similar to the binding of a mouse type II NKT TCR to mouse CD1d (bottom).
with iNKT-cell activation and their overlapping cytokine spectrum may hint to a functional synergy.
ACKNOWLEDGEMENTS This work was supported by NIH grants AI074952 and AI107318.
1 Uldrich AP, Le Nours J, Pellicci DG, Gherardin NA, McPherson KG, Lim RT et al. CD1d-lipid antigen recognition by the gd TCR. Nature Immunol 2013; 14: 1137–1145. 2 Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25: 297–336. 3 Vantourout P, Hayday A. Six-of-the-best: unique contributions of gd T cells to immunology. Nat Rev Immunol 2013; 13: 88–100. 4 Mangan BA, Dunne MR, O’Reilly VP, Dunne PJ, Exley MA, O’Shea D et al. Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vd3 T cells. J Immunol 2013; 191: 30–34. 5 Adams EJ, Chien YH, Garcia KC. Structure of a gd T cell receptor in complex with the nonclassical MHC T22. Science 2005; 308: 227–231. 6 Vavassori S, Kumar A, Wan GS, Ramanjaneyulu GS, Cavallari M, El Daker S et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gammadelta T cells. Nature Immunol 2013; 14: 908–916. 7 Borg NA, Wun KS, Kjer-Nielsen L, Wilce MC, Pellicci DG, Koh R et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 2007; 448: 44–49. 8 Girardi E, Maricic I, Wang J, Mac TT, Iyer P, Kumar V et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nature Immunol 2012; 13: 851–856. 9 Patel O, Pellicci DG, Gras S, Sandoval-Romero ML, Uldrich AP, Mallevaey T et al. Recognition of CD1dsulfatide mediated by a type II natural killer T cell antigen receptor. Nature Immunol 2012; 13: 857–863.
Antiviral responses in adipocytes
Viruses ‘chew the fat’!? Paul Hertzog Immunology and Cell Biology (2014) 92, 100–102; doi:10.1038/icb.2013.91; published online 14 January 2014
T
he innate immune response represents a broad aspect of the host response to environmental stress and homeostatic cues. The stress can take the form of infection, so-called ‘sterile’ inflammatory stimuli (for example, metabolic bi-products such as uric acid and cholesterol) and tumor cells. Examples of homeostatic stimuli include commensal micro-organisms, nutrients and components of extracellular matrix. These stimuli are sensed by a series of so-called pattern recognition receptors (PRRs) that include the Toll like receptors (TLRs), RIGI like helicases (RLHs), NOD-like receptors (NLRs) and emerging family of intracellular DNA sensors (for example, DDX, DHX, Aim2, cGAS, STING) and C-type Lectins.1,2 The innate immune response drives pathways Professor P Hertzog is at Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Victoria 3168, Australia E-mail: [email protected]
Immunology and Cell Biology
that activate antiviral and antibacterial pathways, and sculpt the adaptive immune response via the production of chemokines and cytokines, including tumor necrosis factor (TNF)-a, interleukin-6 (IL6), IL-1b and type I interferons (IFNs). An effective innate response results in resolution of infection, return to homeostasis and priming of an adaptive response or memory should it be required. An uncontrolled innate immune response can lead to acute toxicity and chronic diseases, including autoimmune disease, cancer, and chronic infectious/ inflammatory diseases and other sequelae. There has been considerable interest of late in the intersection of innate immune responses, inflammation and metabolism. Metabolic products such as uric acid and cholesterol can activate NLRP3 inflammasome responses.3,4 Innate pathways contribute to metabolic diseases such as diabetes5 and atherosclerosis.4 Furthermore,
the Gram-negative bacterial cell wall component, lipopolysaccharide (LPS), induces a switch in the metabolic state of macrophages from oxidative phosphorylation to glycolysis, which impacts on the production of the proinflammatory cytokine, IL-1b via succinate production.6 Most of these studies have concentrated on immune cells, principally macrophages, dendrite cell and T cells whose metabolic state is also critical to their immune function.7 The study herein by Yu et al.8 reports that not only immune cells, but also adipocytes, which are important cells in the body’s metabolic state, and their precursor cells express antiviral PRRs such as TLR3, MDA5 and RIG- I, which can respond to cognate ligands by producing IL6, TNFa and type I IFNs. However, stimulation of pre-adipocytes, while generating a strong immune response, inhibits their differentiation into mature adipocytes and decreases the production of
News and Commentaries 101
Virus
PRRs
IL-6, TNFα
PRRs
IFNs α/β Antiviral ISGs
Antiviral ISGs
Pre adipocyte
Adipocyte
Adipokines (leptin, etc.)
Immune response
Metabolism
Figure 1 Viral sensing by adipocytes. Pattern recognition receptors (PRRs) are expressed in adipocytes and pre-adipocytes, and can induce the proinflammatory cytokines TNFa, IL6 and IFNs a/b upon virus recognition. IFNs a/b likely then feed back to induce antiviral ISG expression within these cell types. Additionally, PRR engagement suppresses both pre-adipocyte differentiation into adipocytes and the production of adipokines, thereby influencing both metabolism and the immune response.
adipokines such as leptin, adiponectin and resistin, which are known to modulate immune functions and metabolism. The context of this study is important because reciprocal associations between viral infection and obesity have been implied in the past (infection affecting weight gain or obesity predisposing to infection).9 In this study, Yu et al. demonstrated high expression of the viral-sensing PRRs, TLR3, MDA5 and RIG-I in adipose tissue, whereas TLR7 and 9 had low expression. It would be interesting to also measure the rapidly growing list of intracellular viral DNA sensors2 to ascertain the full potential of these cells’ ability to respond to components of different viruses. Both transfected (activating RLH’s) and extracellular poly I:C (activating TLR3)
activated NF-kB and IRF3 pathways and production of proinflammatory cytokines TNFa, IL6 and type I IFNs via the aforementioned receptors. Furthermore, IFN-induced antiviral genes such as ISG15, 20 50 OAS1 and Mx were also induced by poly I:C, presumably via secondary signaling through IFN receptors, although this was not determined. The authors measured responses by assessing both transcripts and protein levels and used cells from knockout mice or those with PRRs knocked down by RNA interference to prove the modes of action. These results demonstrate that these cells could be an important, perhaps overlooked, contributor to the body’s innate immune response to viral infection—particular given
the significant proportion of these cells in the body (and even more so in obese people). It builds on a body of work showing adipocytes express TLRs 2 and 4 and can response to bacterial ligands with a classical innate immune response.10 While the expression of PRRs and the magnitude of the responses were substantial in both pre-adipocytes and mature adipocytes (the former were, in fact, more robust), the activation of PRRs inhibited the differentiation of precursor cells and their production of adipokines. There is considerable literature on the immunoregulatory roles of adipokines;11 so the impact of activation of adipocyte PRRs in a viral infection could be not only an anticipated significant contribution to the innate immune response Immunology and Cell Biology
News and Commentaries 102
(via classic immunoregulatory cytokines plus adipokines), but also an impact on metabolic state via adipokines (Figure 1). One can speculate on the broad significance of these findings. The reported changes could represent an evolutionarily conserved part of the host response; that is, to dampen metabolism and conserve energy to fight infection, not only by effects on the metabolic state of immune cells as previously reported, but also on parenchymal cells of adipose tissue, whose generation is even impaired. However, this would appear to be at odds with reports that viruses increase adiposity in animal models.9,11 This discrepancy remains to be resolved. Future studies should address several issues including assessment of the response to relevant viral infection, not just isolated products. Other ‘antiviral’ PRRs should also be assessed. It would be interesting to know
the mechanism (which PRR pathway and components) of inhibition of pre-adipocyte differentiation and suppression of adipokines production. Furthermore, it remains to be demonstrated whether these effects observed in vitro translate to the whole animal and from the mouse model to humans.
1 Goutagny N, Fitzgerald KA. Pattern recognition receptors: an update. Expert Rev Clin Immunol 2006; 2: 569–583. 2 Keating SE, Baran M, Bowie AG. Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol 2011; 32: 574–581. 3 Rock KL, Kataoka H, Lai JJ. Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol 2013; 9: 13–23. 4 Duewell P, Kono H, Rayner KJ, Sirois CM Vladimer G, Bauernfeind FG et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464: 1357–1361.
5 Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1b in type 2 diabetes. Nat Immunol 2010; 11: 897–904. 6 Tannahill GM, Curtis AM, Adamik J, PalssonMcDermott EM, McGettrick AF, Goel G et al. Succinate is an inflammatory signal that induces IL-1b through HIF-1a. Nature 2013; 496: 238–242. 7 McGettrick AF, O’Neill LA. How metabolism generates signals during innate immunity and inflammation. J Biol Chem 2013; 288: 22893–22898. 8 Yu L, Yan K, Liu P, Li N, Liu Z, Zhu W et al. Pattern recognition receptor-initiated innate antiviral response in mouse adipose cells. Immunol Cell Biol 2014; 92: 105–115. 9 Hegde V, Dhurandhar NV. Microbes and obesity— interrelationship between infection, adipose tissue and the immune system. Clin Microbiol Infect 2013; 19: 314–320. 10 Schaffler A, Scholmerich J, Slazberger B. Adipose tissue as an immunological organ: Toll Like receptors, C1q/TNFs and CTRPs. Trends Immunol 2007; 28: 393–399. 11 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772–783.
GADD34 in granulocyte production
Linking stress granulopoiesis to protein synthesis through GADD34 Hrishikesh M Mehta and Seth J Corey Immunology and Cell Biology (2014) 92, 102–104; doi:10.1038/icb.2013.107; published online 14 January 2014
n the current issue, Nishio et al.1 propose a novel role for the growth arrest and DNA damage inducible 34 (GADD34) in the suppression of myelopoiesis and stress granulopoiesis. They observed that older Gadd34 / mice displayed an increase in both immature (Gr1low CD11b þ ) and mature granulocytes (Gr1hi CD11b þ ). This age-dependent expansion was also observed in hematopoietic stem cells (HSCs) and early myeloid progenitors. They showed that GADD34 expression was highest in HSCs, which suggests that GADD34 mediates its inhibition of myelopoiesis at a stem cell stage. The authors attributed the expansion observed in the Gadd34 / mice to an age-related increase in the gut microbiome, which triggers production of granulocyte colony-stimulating factor (GCSF), the most
I
Dr HM Mehta and Professor SJ Corey are at Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA E-mail: [email protected]
Immunology and Cell Biology
important growth factor for production of granulocytes. Further, they provide a mechanism for GADD34-mediated suppression of GCSF Receptor signaling, through inhibition of activation of Lyn and STAT3, two important signaling molecules for GCSF Receptor-mediated proliferation and differentiation of myeloid progenitors (Figure 1).2,3 While GADD34 expression was first identified through a screen for genes expressed following genotoxic injury due to irradiation or alkylating agents,4 subsequent studies suggest its primary role in the unfolded protein response (UPR). Upregulation of GADD34 occurs during UPR, an evolutionarily conserved pathway to protect cells. Unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen, which triggers a chain reaction of biochemical events to limit cell injury. Prolonged activation of UPR leads, however, to apoptosis. An important sensor of the
UPR is the double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) (Figure 1). PERK activation involves dissociation of B-cell immunoglobulin heavy chain-binding protein (BiP), a molecular chaperone that binds to unfolded proteins in the ER. Dissociation of BiP drives oligomerization of PERK, resulting in the trans-autophosphorylation of PERK. Phosphorylated PERK then phosphorylates elongation initiation factor 2a (eIF2a), which downregulates protein expression. Although eIF2a expression shuts off translation of most mRNAs, it enhances the translation of activating transcription factor 4 (ATF-4) mRNA, which under non-stressed conditions is not translated to the ATF-4 protein.5 ATF-4 then drives expression of C/EBP homologous protein (CHOP) and GADD34. CHOP also induces GADD34, further increasing its expression.6 GADD34 serves as an inducible regulatory subunit of the PP1 holoenzyme and
