Macrophage PPAR-γ suppresses long-term lung fibrotic sequelae following acute influenza infection


Autoři: Su Huang aff001;  Nick P. Goplen aff001;  Bibo Zhu aff001;  In Su Cheon aff001;  Youngmin Son aff001;  Zheng Wang aff001;  Chaofan Li aff001;  Qigang Dai aff001;  Li Jiang aff001;  Min Xiang aff001;  Eva M. Carmona aff001;  Robert Vassallo aff001;  Andrew H. Limper aff001;  Jie Sun aff001
Působiště autorů: Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Rochester, Minnesota, United States of America aff001;  Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Rochester, Minnesota, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223430

Souhrn

Influenza virus causes a heterogeneous respiratory infectious disease ranging from self-limiting symptoms to non-resolving pathology in the lungs. Worldwide, seasonal influenza infections claim ~500,000 lives annually. Recent reports describe pathologic pulmonary sequelae that result in remodeling the architecture of lung parenchyma following respiratory infections. These dysfunctional recovery processes that disproportionately impact the elderly have been understudied. Macrophages are involved in tissue remodeling and are critical for survival of severe influenza infection. Here, we found intrinsic deficiency of the nuclear receptor PPAR-γ in myeloid cells delayed the resolution of pulmonary inflammation following influenza infection. Mice with myeloid cell-specific PPAR-γ deficiency subsequently presented with increased influenza-induced deposition of pulmonary collagen compared to control mice. This dysfunctional lung remodeling was progressive and sustained for at least 3 months following infection of mice with myeloid PPAR-γ deficiency. These progressive changes were accompanied by a pro-fibrotic gene signature from lung macrophages and preceded by deficiencies in activation of genes involved with damage repair. Importantly similar aberrant gene expression patterns were also found in a secondary analysis of a study where macrophages were isolated from patients with fibrotic interstitial lung disease. Quite unexpectedly, mice with PPAR-γ deficient macrophages were more resistant to bleomycin-induced weight loss whereas extracellular matrix deposition was unaffected compared to controls. Therefore PPAR-γ expression in macrophages may be a pathogen-specific limiter of organ recovery rather than a ubiquitous effector pathway in response to generic damage.

Klíčová slova:

Alveolar macrophages – Collagens – Gene expression – Influenza – Influenza viruses – Macrophages – Pulmonary fibrosis – Respiratory infections


Zdroje

1. Ruf BR, Knuf M. The burden of seasonal and pandemic influenza in infants and children. Eur J Pediatr. 2014;173(3):265–76. doi: 10.1007/s00431-013-2023-6 23661234; PubMed Central PMCID: PMC3930829.

2. Keeler SP, Agapov EV, Hinojosa ME, Letvin AN, Wu K, Holtzman MJ. Influenza A Virus Infection Causes Chronic Lung Disease Linked to Sites of Active Viral RNA Remnants. J Immunol. 2018;201(8):2354–68. doi: 10.4049/jimmunol.1800671 30209189; PubMed Central PMCID: PMC6179922.

3. Zhang Y, Mao D, Keeler SP, Wang X, Wu K, Gerovac BJ, et al. Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost. J Immunol. 2019;202(8):2332–47. Epub 2019/02/26. doi: 10.4049/jimmunol.1801491 30804041; PubMed Central PMCID: PMC6456410.

4. Yoo JK, Kim TS, Hufford MM, Braciale TJ. Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol. 2013;132(6):1263–76; quiz 77. doi: 10.1016/j.jaci.2013.06.006 23915713; PubMed Central PMCID: PMC3844062.

5. Desai O, Winkler J, Minasyan M, Herzog EL. The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Frontiers in medicine. 2018;5:43. Epub 2018/04/05. doi: 10.3389/fmed.2018.00043 29616220; PubMed Central PMCID: PMC5869935.

6. Wang Z, Wang S, Goplen NP, Li C, Cheon IS, Dai Q, et al. PD-1(hi) CD8(+) resident memory T cells balance immunity and fibrotic sequelae. Sci Immunol. 2019;4(36). Epub 2019/06/16. doi: 10.1126/sciimmunol.aaw1217 31201259.

7. Sun J, Madan R, Karp CL, Braciale TJ. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med. 2009;15(3):277–84. Epub 2009/02/24. doi: 10.1038/nm.1929 19234462; PubMed Central PMCID: PMC2693210.

8. Wong SS, Oshansky CM, Guo XJ, Ralston J, Wood T, Seeds R, et al. Severe Influenza Is Characterized by Prolonged Immune Activation: Results From the SHIVERS Cohort Study. J Infect Dis. 2018;217(2):245–56. Epub 2017/11/08. doi: 10.1093/infdis/jix571 29112724.

9. Braciale TJ, Sun J, Kim TS. Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol. 2012;12(4):295–305. doi: 10.1038/nri3166 22402670; PubMed Central PMCID: PMC3364025.

10. Sun J, Braciale TJ. Role of T cell immunity in recovery from influenza virus infection. Curr Opin Virol. 2013;3(4):425–9. doi: 10.1016/j.coviro.2013.05.001 23721865; PubMed Central PMCID: PMC3804899.

11. Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol. 2016;38(4):471–82. doi: 10.1007/s00281-016-0558-0 26965109; PubMed Central PMCID: PMC4896975.

12. Guo XJ, Thomas PG. New fronts emerge in the influenza cytokine storm. Semin Immunopathol. 2017;39(5):541–50. Epub 2017/05/31. doi: 10.1007/s00281-017-0636-y 28555383; PubMed Central PMCID: PMC5580809.

13. Zammit DJ, Turner DL, Klonowski KD, Lefrancois L, Cauley LS. Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration. Immunity. 2006;24(4):439–49. Epub 2006/04/19. doi: 10.1016/j.immuni.2006.01.015 16618602; PubMed Central PMCID: PMC2861289.

14. Jelley-Gibbs DM, Brown DM, Dibble JP, Haynes L, Eaton SM, Swain SL. Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation. J Exp Med. 2005;202(5):697–706. Epub 2005/09/09. doi: 10.1084/jem.20050227 16147980; PubMed Central PMCID: PMC2212871.

15. Kim TS, Hufford MM, Sun J, Fu YX, Braciale TJ. Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection. J Exp Med. 2010;207(6):1161–72. Epub 2010/06/02. doi: 10.1084/jem.20092017 20513748; PubMed Central PMCID: PMC2882836.

16. Pociask DA, Robinson KM, Chen K, McHugh KJ, Clay ME, Huang GT, et al. Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection. Am J Pathol. 2017;187(4):851–63. doi: 10.1016/j.ajpath.2016.12.012 28193481; PubMed Central PMCID: PMC5397680.

17. Qiao J, Zhang M, Bi J, Wang X, Deng G, He G, et al. Pulmonary fibrosis induced by H5N1 viral infection in mice. Respir Res. 2009;10:107. doi: 10.1186/1465-9921-10-107 19909524; PubMed Central PMCID: PMC2783028.

18. Kanegai CM, Xi Y, Donne ML, Gotts JE, Driver IH, Amidzic G, et al. Persistent Pathology in Influenza-Infected Mouse Lungs. Am J Respir Cell Mol Biol. 2016;55(4):613–5. doi: 10.1165/rcmb.2015-0387LE 27689795; PubMed Central PMCID: PMC5070109.

19. Goplen N, Karim MZ, Liang Q, Gorska MM, Rozario S, Guo L, et al. Combined sensitization of mice to extracts of dust mite, ragweed, and Aspergillus species breaks through tolerance and establishes chronic features of asthma. J Allergy Clin Immunol. 2009;123(4):925–32 e11. Epub 2009/04/08. doi: 10.1016/j.jaci.2009.02.009 19348928; PubMed Central PMCID: PMC2683988.

20. Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327(5963):291–5. Epub 2010/01/16. doi: 10.1126/science.1183021 20075244; PubMed Central PMCID: PMC3645875.

21. Iwasaki A, Foxman EF, Molony RD. Early local immune defences in the respiratory tract. Nat Rev Immunol. 2017;17(1):7–20. doi: 10.1038/nri.2016.117 27890913; PubMed Central PMCID: PMC5480291.

22. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science. 2012;335(6071):936–41. Epub 2012/03/01. doi: 10.1126/science.1214935 22363001; PubMed Central PMCID: PMC3564547.

23. Rawlins EL. Stem cells: Emergency back-up for lung repair. Nature. 2015;517(7536):556–7. Epub 2015/01/30. doi: 10.1038/517556a 25631438.

24. Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA, Yamamoto Y, et al. p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature. 2015;517(7536):616–20. Epub 2014/11/11. doi: 10.1038/nature13903 25383540.

25. Sueblinvong V, Neujahr DC, Mills ST, Roser-Page S, Ritzenthaler JD, Guidot D, et al. Predisposition for disrepair in the aged lung. Am J Med Sci. 2012;344(1):41–51. Epub 2011/12/17. doi: 10.1097/MAJ.0b013e318234c132 22173045; PubMed Central PMCID: PMC3395069.

26. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature. 2015;517(7536):621–5. doi: 10.1038/nature14112 25533958; PubMed Central PMCID: PMC4312207.

27. Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol. 2014;14(2):81–93. Epub 2014/01/22. doi: 10.1038/nri3600 24445666.

28. Italiani P, Boraschi D. New Insights Into Tissue Macrophages: From Their Origin to the Development of Memory. Immune Netw. 2015;15(4):167–76. Epub 2015/09/04. doi: 10.4110/in.2015.15.4.167 26330802; PubMed Central PMCID: PMC4553254.

29. Faz-Lopez B, Morales-Montor J, Terrazas LI. Role of Macrophages in the Repair Process during the Tissue Migrating and Resident Helminth Infections. Biomed Res Int. 2016;2016:8634603. Epub 2016/09/21. doi: 10.1155/2016/8634603 27648452; PubMed Central PMCID: PMC5014929.

30. Wynn TA, Vannella KM. Macrophages in Tissue Repair, Regeneration, and Fibrosis. Immunity. 2016;44(3):450–62. Epub 2016/03/18. doi: 10.1016/j.immuni.2016.02.015 26982353; PubMed Central PMCID: PMC4794754.

31. Guilliams M, Lambrecht BN, Hammad H. Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013;6(3):464–73. Epub 2013/04/04. doi: 10.1038/mi.2013.14 23549447.

32. Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med. 2017;214(8):2387–404. Epub 2017/07/12. doi: 10.1084/jem.20162152 28694385; PubMed Central PMCID: PMC5551573.

33. Zhang L, Chawla A. Role of PPARgamma in macrophage biology and atherosclerosis. Trends Endocrinol Metab. 2004;15(10):500–5. Epub 2004/11/16. doi: 10.1016/j.tem.2004.10.006 15541649.

34. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19(5):557–66. Epub 2013/05/09. doi: 10.1038/nm.3159 23652116; PubMed Central PMCID: PMC3870016.

35. Schneider C, Nobs SP, Heer AK, Kurrer M, Klinke G, van Rooijen N, et al. Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection. PLoS Pathog. 2014;10(4):e1004053. doi: 10.1371/journal.ppat.1004053 24699679; PubMed Central PMCID: PMC3974877.

36. Schneider C, Nobs SP, Kurrer M, Rehrauer H, Thiele C, Kopf M. Induction of the nuclear receptor PPAR-gamma by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. 2014;15(11):1026–37. doi: 10.1038/ni.3005 25263125.

37. Huang S, Jiang L, Cheon IS, Sun J. Targeting Peroxisome Proliferator-Activated Receptor-Gamma Decreases Host Mortality After Influenza Infection in Obese Mice. Viral immunology. 2019;32(4):161–9. Epub 2019/04/23. doi: 10.1089/vim.2019.0016 31009317; PubMed Central PMCID: PMC6534095.

38. Huang S, Zhu B, Cheon IS, Goplen NP, Jiang L, Zhang R, et al. PPAR-gamma in macrophages limits pulmonary inflammation and promotes host recovery following respiratory viral infection. J Virol. 2019. Epub 2019/02/23. doi: 10.1128/JVI.00030-19 30787149.

39. Hua L, Yao S, Pham D, Jiang L, Wright J, Sawant D, et al. Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection. J Virol. 2013;87(21):11884–93. doi: 10.1128/JVI.01461-13 23986597; PubMed Central PMCID: PMC3807312.

40. Jung MY, Kang JH, Hernandez DM, Yin X, Andrianifahanana M, Wang Y, et al. Fatty acid synthase is required for profibrotic TGF-beta signaling. FASEB J. 2018;32(7):3803–15. Epub 2018/02/25. doi: 10.1096/fj.201701187R 29475397; PubMed Central PMCID: PMC5998981.

41. Cheon IS, Son YM, Jiang L, Goplen NP, Kaplan MH, Limper AH, et al. Neonatal hyperoxia promotes asthma-like features through IL-33-dependent ILC2 responses. J Allergy Clin Immunol. 2018;142(4):1100–12. doi: 10.1016/j.jaci.2017.11.025 29253513; PubMed Central PMCID: PMC6003836.

42. Yao S, Jiang L, Moser EK, Jewett LB, Wright J, Du J, et al. Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection. Mucosal Immunol. 2015;8(4):746–59. Epub 2014/12/04. doi: 10.1038/mi.2014.106 25465101; PubMed Central PMCID: PMC4632244.

43. Jiang L, Yao S, Huang S, Wright J, Braciale TJ, Sun J. Type I IFN signaling facilitates the development of IL-10-producing effector CD8(+) T cells during murine influenza virus infection. Eur J Immunol. 2016;46(12):2778–88. doi: 10.1002/eji.201646548 27701741; PubMed Central PMCID: PMC5184847.

44. Shi Y, Gochuico BR, Yu G, Tang X, Osorio JC, Fernandez IE, et al. Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-beta receptor I internalization and inhibiting transforming growth factor-beta1 signaling. Am J Respir Crit Care Med. 2013;188(7):831–41. Epub 2013/08/09. doi: 10.1164/rccm.201303-0434OC 23924348; PubMed Central PMCID: PMC3826270.

45. Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol. 2008;40(3):362–82. Epub 2007/10/16. doi: 10.1016/j.biocel.2007.08.011 17936056; PubMed Central PMCID: PMC2323681.

46. Chaudhary NI, Schnapp A, Park JE. Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model. Am J Respir Crit Care Med. 2006;173(7):769–76. Epub 2006/01/18. doi: 10.1164/rccm.200505-717OC 16415276.

47. Mineo G, Ciccarese F, Modolon C, Landini MP, Valentino M, Zompatori M. Post-ARDS pulmonary fibrosis in patients with H1N1 pneumonia: role of follow-up CT. Radiol Med. 2012;117(2):185–200. Epub 2011/10/25. doi: 10.1007/s11547-011-0740-3 22020433.

48. Singh V, Sharma BB, Patel V. Pulmonary sequelae in a patient recovered from swine flu. Lung India. 2012;29(3):277–9. Epub 2012/08/25. doi: 10.4103/0970-2113.99118 22919170; PubMed Central PMCID: PMC3424870.

49. Li P, Zhang JF, Xia XD, Su DJ, Liu BL, Zhao DL, et al. Serial evaluation of high-resolution CT findings in patients with pneumonia in novel swine-origin influenza A (H1N1) virus infection. Br J Radiol. 2012;85(1014):729–35. Epub 2011/12/15. doi: 10.1259/bjr/85580974 22167502; PubMed Central PMCID: PMC3474108.

50. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis-a review of current and novel pharmacotherapies. J Thorac Dis. 2015;7(3):499–519. doi: 10.3978/j.issn.2072-1439.2015.01.17 25922733; PubMed Central PMCID: PMC4387423.

51. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018;378(19):1811–23. doi: 10.1056/NEJMra1705751 29742380.

52. Molyneaux PL, Maher TM. The role of infection in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir Rev. 2013;22(129):376–81. doi: 10.1183/09059180.00000713 23997064.

53. Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. Journal of Experimental Medicine. 2017;214(8):2387–404. doi: 10.1084/jem.20162152 28694385 PubMed PMID: WOS:000407076300016.

54. Ginhoux F, Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity. 2016;44(3):439–49. Epub 2016/03/18. doi: 10.1016/j.immuni.2016.02.024 26982352.

55. Aldridge JR Jr., Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci U S A. 2009;106(13):5306–11. doi: 10.1073/pnas.0900655106 19279209; PubMed Central PMCID: PMC2664048.

56. Lin KL, Suzuki Y, Nakano H, Ramsburg E, Gunn MD. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol. 2008;180(4):2562–72. doi: 10.4049/jimmunol.180.4.2562 18250467.

57. Desai TJ, Brownfield DG, Krasnow MA. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature. 2014;507(7491):190–4. doi: 10.1038/nature12930 24499815; PubMed Central PMCID: PMC4013278.

58. Solleti SK, Simon DM, Srisuma S, Arikan MC, Bhattacharya S, Rangasamy T, et al. Airway epithelial cell PPARgamma modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice. Am J Physiol Lung Cell Mol Physiol. 2015;309(3):L293–304. Epub 2015/05/31. doi: 10.1152/ajplung.00287.2014 26024894; PubMed Central PMCID: PMC4525123.

59. Pebody RG, McLean E, Zhao H, Cleary P, Bracebridge S, Foster K, et al. Pandemic Influenza A (H1N1) 2009 and mortality in the United Kingdom: risk factors for death, April 2009 to March 2010. Euro Surveill. 2010;15(20). Epub 2010/05/28. 20504388.

60. Gopal R, Mendy A, Marinelli MA, Richwalls LJ, Seger PJ, Patel S, et al. Peroxisome Proliferator-Activated Receptor Gamma (PPAR) Suppresses Inflammation and Bacterial Clearance during Influenza-Bacterial Super-Infection. Viruses. 2019;11(6). Epub 2019/06/05. doi: 10.3390/v11060505 31159430.

61. Hamilton RF Jr., Li L, Felder TB, Holian A. Bleomycin induces apoptosis in human alveolar macrophages. Am J Physiol. 1995;269(3 Pt 1):L318–25. Epub 1995/09/11. doi: 10.1152/ajplung.1995.269.3.L318 7573464.

62. Della Latta V, Cecchettini A, Del Ry S, Morales MA. Bleomycin in the setting of lung fibrosis induction: From biological mechanisms to counteractions. Pharmacol Res. 2015;97:122–30. Epub 2015/05/12. doi: 10.1016/j.phrs.2015.04.012 25959210.

63. Lakatos HF, Thatcher TH, Kottmann RM, Garcia TM, Phipps RP, Sime PJ. The Role of PPARs in Lung Fibrosis. PPAR Res. 2007;2007:71323. Epub 2007/08/22. doi: 10.1155/2007/71323 17710235; PubMed Central PMCID: PMC1940051.


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