EDITORIALS Multifaceted Role for IL-17A in the Pathogenesis of Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) is a major global health issue that is predominantly caused by cigarette smoking. Pathologically, COPD is characterized as a chronic inﬂammatory condition that is associated with the accumulation of innate and adaptive immune cells in the airways, along with increased systemic inﬂammation. As the disease progresses, inﬂammation increases and patients become more susceptible to acute exacerbations of COPD, caused primarily by respiratory pathogens, which further increase local and systemic inﬂammation. Antiinﬂammatory agents such as corticosteroids are used to treat symptoms and may help to reduce exacerbation rates; however, they do not effectively reduce neutrophilic inﬂammation that persists despite escalating use of inhaled corticosteroids (1). As neutrophil numbers increase with COPD severity, so does the release of neutrophil degranulation products, including neutrophil elastase and matrix metalloproteinases such as MMP-9 (1). Macrophages play a central role in clearance of apoptotic neutrophils, and their function is compromised in a microenvironment in which there is excessive oxidative and carbonyl stress (2), leading to a deﬁciency in efferocytosis of apoptotic cells (3). Macrophages also interact with carbonyl-adduct-modiﬁed extracellular matrix proteins, which impair their ability to clear apoptotic neutrophils (4). Hence, the persistence of neutrophilic inﬂammation in COPD is attributable to continual recruitment of leukocytes and compromised clearance of exhausted neutrophils resulting from excessive oxidative stress promotes indiscriminate degranulation and tissue damage. As IL-17A is a central cytokine that regulates neutrophilic inﬂammation in the airways (5), there has been increasing interest in deﬁning its role in COPD. IL-17A1 cells have been shown to be increased in the bronchial submucosa of chronic smokers and stable patients with COPD (6, 7), and genetic ablation of the IL-17 receptor (IL-17R) in experimental cigarette smoke models protected mice against the development of emphysema (8). Neutrophilic inﬂammation induced by cigarette smoke exposure is potently suppressed in mice deﬁcient in IL-17A (9) and in response to neutralization with a blocking antibody (10). We have recently screened for molecular markers associated with the persistence of inﬂammation in an experimental cigarette smoking cessation model and identiﬁed IL-17A and serum amyloid A as two markers that did not signiﬁcantly reduce with cessation (11). We have also shown that serum amyloid A initiates neutrophilic inﬂammation in the airways via IL-17A–dependent mechanisms (12) and polarizes macrophages toward a phenotype that produces more Th17-skewing cytokines (13). In this issue of the Journal, Roos and colleagues (pp. 1232–1241) demonstrate increased IL-17A immunoreactivity in severe COPD (Global Initiative for Chronic Obstructive Lung Disease III-IV) compared with mild to moderate COPD and control smokers. This increase was independent of the number of IL17A1 cells, suggesting increased production of IL-17A in severe COPD (14).
This has important implications, as the number of IL-17A1 cells in the submucosa may not necessarily reﬂect the signiﬁcance of the key cytokine in regulating inﬂammation in COPD. In addition, they demonstrate that IL-17A signaling is required for the formation of lymphoid follicles by regulating the expression of the B-cell–attracting chemokine C-X-C motif ligand (CXCL)12 in mice exposed to cigarette smoke. Increased pulmonary expression of CXCL12 was also detected in lymphoid follicles in end-stage COPD. Lymphoid follicles have been implicated in the pathogenesis of COPD through B-cell–mediated inﬂammation and autoantibody responses that may induce alveolar tissue destruction (15). However, as lymphoid aggregates in lung may also contribute to beneﬁcial host immunity to respiratory infections and tumor eradication, further work is needed to elucidate their function in COPD. The inhibition of lymphoid follicles by neutralizing CXCL13 has previously been shown to selectively reduce alveolar tissue destruction during cigarette smoke exposure without signiﬁcant changes in lung inﬂammation, alveolar diameter, and airway wall remodeling (15). Whether CXCL12 or CXCL13 are dominant for lymphoid neogenesis remains to be elucidated, but Roos and colleagues demonstrate a greater dependency on CXCL12 in IL-17A knockout mice. In addition to regulating neutrophilic inﬂammation and lymphoid neogenesis, IL-17A has also been shown to regulate the increased accumulation of airway macrophages in response to cigarette smoke exposure (8). Using nonobese diabetic/severe combined immunodeﬁciency mice, we have shown that the accumulation of macrophages in response to cigarette smoke can occur independent of functional B and T cells (unpublished data). In this study, we have tracked cellular sources of IL-17A in cigarette smoke-exposed mice and identiﬁed innate and nonconventional T-cell sources of IL-17A including natural killer (NK), NK T, and gd T cells. Roos and colleagues also investigated cellular sources of IL-17A and colocalized IL-17A1 cells in the submucosa with tryptase positive mast cells. This is an important ﬁnding that supports a role for innate sources of IL-17A; however, given that nonconventional T cells are infrequent in the lung mucosa, immunohistochemical analyses may lack the sensitivity to reveal their relative contribution to IL-17A expression in severe COPD. A greater understanding of why IL-17A persists after cessation of cigarette smoke exposure is needed, as many patients with severe COPD have already quit smoking. It will also be of great interest to better deﬁne the predominant cellular sources of IL-17A in endstage COPD, as this may help to not only combat the persistent recruitment of neutrophils but also combat chronic macrophage and lymphoid follicle accumulation. By identifying the predominant cellular subset, it may be possible to selectively reduce pathogenic IL-17A signaling without completely disabling IL-17A–regulated pathways that are essential for host immunity to respiratory infections. Because the majority of patients with severe COPD are
Am J Respir Crit Care Med Vol 191, Iss 11, pp 1213–1225, Jun 1, 2015 Internet address: www.atsjournals.org
EDITORIALS chronically colonized and are susceptible to frequent exacerbations, increased IL-17A expression in COPD is clearly failing to control respiratory infection and is likely to maintain chronic inﬂammation. Whether targeting IL-17A can safely reduce chronic inﬂammation in COPD without compromising host immunity to respiratory infection warrants further investigation and may depend on selective targeting of innate cellular subsets. n Author disclosures are available with the text of this article at www.atsjournals.org. Steven Bozinovski, Ph.D. Ross Vlahos, Ph.D. School of Health Sciences and Health Innovations Research Institute Royal Melbourne Institute of Technology University Bundoora, Victoria, Australia and Lung Health Research Centre The University of Melbourne Parkville, Victoria, Australia
References 1. Vlahos R, Wark PA, Anderson GP, Bozinovski S. Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD. PLoS ONE 2012;7:e33277. 2. Bozinovski S, Vlahos R, Zhang Y, Lah LC, Seow HJ, Mansell A, Anderson GP. Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity. Am J Respir Cell Mol Biol 2011;45:229–236. 3. Hodge S, Hodge G, Ahern J, Jersmann H, Holmes M, Reynolds PN. Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2007;37:748–755. 4. Kirkham PA, Spooner G, Rahman I, Rossi AG. Macrophage phagocytosis of apoptotic neutrophils is compromised by matrix proteins modiﬁed by cigarette smoke and lipid peroxidation products. Biochem Biophys Res Commun 2004;318:32–37. 5. Ivanov S, Bozinovski S, Bossios A, Valadi H, Vlahos R, Malmhall ¨ C, Sjostrand ¨ M, Kolls JK, Anderson GP, Linden ´ A. Functional relevance of the IL-23-IL-17 axis in lungs in vivo. Am J Respir Cell Mol Biol 2007; 36:442–451. 6. Di Stefano A, Caramori G, Gnemmi I, Contoli M, Vicari C, Capelli A, Magno F, D’Anna SE, Zanini A, Brun P, et al. T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable
chronic obstructive pulmonary disease patients. Clin Exp Immunol 2009;157:316–324. 7. Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V, Rugman P, McCormick M, Woods J, May R, Sleeman MA, et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 2010;138:1140–1147. 8. Chen K, Pociask DA, McAleer JP, Chan YR, Alcorn JF, Kreindler JL, Keyser MR, Shapiro SD, Houghton AM, Kolls JK, et al. IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke. PLoS ONE 2011;6: e20333. 9. Chang Y, Al-Alwan L, Audusseau S, Chouiali F, Carlevaro-Fita J, Iwakura Y, Baglole CJ, Eidelman DH, Hamid Q. Genetic deletion of IL-17A reduces cigarette smoke-induced inﬂammation and alveolar type II cell apoptosis. Am J Physiol Lung Cell Mol Physiol 2014;306: L132–L143. 10. Shen N, Wang J, Zhao M, Pei F, He B. Anti-interleukin-17 antibodies attenuate airway inﬂammation in tobacco-smoke-exposed mice. Inhal Toxicol 2011;23:212–218. 11. Hansen MJ, Chan SP, Langenbach SY, Dousha LF, Jones JE, Yatmaz S, Seow HJ, Vlahos R, Anderson GP, Bozinovski S. IL-17A and serum amyloid A are elevated in a cigarette smoke cessation model associated with the persistence of pigmented macrophages, neutrophils and activated NK cells. PLoS ONE 2014;9:e113180. 12. Anthony D, Seow HJ, Uddin M, Thompson M, Dousha L, Vlahos R, Irving LB, Levy BD, Anderson GP, Bozinovski S. Serum amyloid A promotes lung neutrophilia by increasing IL-17A levels in the mucosa and gd T cells. Am J Respir Crit Care Med 2013;188: 179–186. 13. Anthony D, McQualter JL, Bishara M, Lim EX, Yatmaz S, Seow HJ, Hansen M, Thompson M, Hamilton JA, Irving LB, et al. SAA drives proinﬂammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling. FASEB J [online ahead of print] 20 May 2014; DOI: 10.1096/fj.14-250332. 14. Roos AB, Sanden ´ C, Mori M, Bjermer L, Stampﬂi MR, Erjefalt ¨ JS. IL-17A is elevated in end-stage chronic obstructive pulmonary disease and contributes to cigarette smoke–induced lymphoid neogenesis. Am J Respir Crit Care Med 2015;191:1232–1241. 15. Bracke KR, Verhamme FM, Seys LJ, Bantsimba-Malanda C, Cunoosamy DM, Herbst R, Hammad H, Lambrecht BN, Joos GF, Brusselle GG. Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:343–355.
Copyright © 2015 by the American Thoracic Society
Is Bronchiolitis Obliterans after Hematopoietic Stem Cell Transplantation Reversible? Hematopoietic stem cell transplantation (HSCT) is a treatment modality for thousands of patients annually, and most commonly for hematologic and lymphoid malignancies (1). Infectious and noninfectious pulmonary complications may occur in more than 30% of patients (2). After allogeneic HSCT, manifestations of acute and chronic graft versus host disease (GVHD) are major contributors to morbidity and mortality. Improvements in supportive care and modiﬁcations in induction protocols and preventive measures for infections and GVHD have decreased mortality over time (3). Complications associated with acute GVHD include diffuse alveolar damage
and interstitial pneumonitis. As a complication occurring months to years after HSCT, bronchiolitis obliterans is a potentially devastating process of inﬂammation and ﬁbroproliferative occlusion of small airways, leading to progressive airﬂow obstruction. Although biopsy is needed for histologic conﬁrmation, bronchiolitis obliterans syndrome (BOS) refers to progressive airﬂow obstruction on pulmonary function testing (FEV1 decline . 20% from baseline) in the appropriate clinical setting. High-resolution computed tomography scanning is also commonly used for diagnosis and may show air trapping, bronchial wall thickening, and
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 11 | June 1 2015