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Immunomodulatory Regulation of Lung Regeneration and Repair

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Stem Cells in the Lung

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

To protect against the wide variety of microorganisms, dusts and pollutants that we continually inhale during respiration the lung is fortified by a network of mucosal innate immune cells. Innate immune cells in the lung have evolved to mediate complex immune responses to protect the body from bacteria, viruses, and parasites. However, evidence is mounting that specialized innate immune cells have also evolved to play a critical role in epithelial regeneration and homeostasis. Successful tissue regeneration in the lung requires precise coordination of multiple processes, including eliminating pathogens and scavenging cellular debris, immune modulation, and proliferation and activation of progenitor cells. Among the innate immune cells in the lung, macrophages and type 2 innate lymphoid cells (ILCs) have emerged as effector cells that serve to regulate the regenerative capacity of the lung in response to inflammation or infection. In this review we discuss the current understanding of the roles of these innate immune cells in tissue regeneration and postulate on how an imbalance in the immune response fails to effectively resolve inflammation and restore normal lung homeostasis in chronic respiratory diseases.

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References

  1. Werner JL, Steele C (2014) Innate receptors and cellular defense against pulmonary infections. J Immunol 193(8):3842–3850

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604

    Article  CAS  PubMed  Google Scholar 

  3. Brancato SK, Albina JE (2011) Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol 178(1):19–25

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S et al (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115(1):56–65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi BS et al (2011) Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 22(2):317–326

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH (2011) Macrophages in skin injury and repair. Immunobiology 216(7):753–762

    Article  PubMed  Google Scholar 

  7. Walker JA, Barlow JL, McKenzie AN (2013) Innate lymphoid cells—how did we miss them? Nat Rev Immunol 13(2):75–87

    Article  CAS  PubMed  Google Scholar 

  8. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Davies LC, Jenkins SJ, Allen JE, Taylor PR (2013) Tissue-resident macrophages. Nat Immunol 14(10):986–995

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Gordon S, Pluddemann A, Martinez Estrada F (2014) Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev 262(1):36–55

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90

    Article  CAS  PubMed  Google Scholar 

  12. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38(4):792–804

    Article  CAS  PubMed  Google Scholar 

  13. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. van oud Alblas AB, van Furth R (1979) Origin, Kinetics, and characteristics of pulmonary macrophages in the normal steady state. J Exp Med 149(6):1504–1518

    Article  Google Scholar 

  15. Guilliams M, De Kleer I, Henri S, Post S, Vanhoutte L, De Prijck S et al (2013) Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med 210(10):1977–1992

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Maus UA, Janzen S, Wall G, Srivastava M, Blackwell TS, Christman JW et al (2006) Resident alveolar macrophages are replaced by recruited monocytes in response to endotoxin-induced lung inflammation. Am J Respir Cell Mol Biol 35(2):227–235

    Article  CAS  PubMed  Google Scholar 

  17. Tarling JD, Lin HS, Hsu S (1987) Self-renewal of pulmonary alveolar macrophages: evidence from radiation chimera studies. J Leukoc Biol 42(5):443–446

    CAS  PubMed  Google Scholar 

  18. Franke-Ullmann G, Pfortner C, Walter P, Steinmuller C, Lohmann-Matthes ML, Kobzik L (1996) Characterization of murine lung interstitial macrophages in comparison with alveolar macrophages in vitro. J Immunol 157(7):3097–3104

    CAS  PubMed  Google Scholar 

  19. Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944

    Article  CAS  PubMed  Google Scholar 

  20. Nathan CF, Hibbs JB Jr (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 3(1):65–70

    Article  CAS  PubMed  Google Scholar 

  21. Fantone JC, Ward PA (1982) Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol 107(3):395–418

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Hickman-Davis JM, O’Reilly P, Davis IC, Peti-Peterdi J, Davis G, Young KR et al (2002) Killing of Klebsiella pneumoniae by human alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 282:L944–L956

    Article  CAS  PubMed  Google Scholar 

  23. Dhaliwal K, Scholefield E, Ferenbach D, Gibbons M, Duffin R, Dorward DA et al (2012) Monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury. Am J Respir Crit Care Med 186(6):514–524

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Rodgers B, Mims CA (1981) Interaction of influenza virus with mouse macrophages. Infect Immun 31(2):751–757

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Cirino NM, Panuska JR, Villani A, Taraf H, Rebert NA, Merolla R et al (1993) Restricted replication of respiratory syncytial virus in human alveolar macrophages. J Gen Virol 74(Pt 8):1527–1537

    Article  CAS  PubMed  Google Scholar 

  26. Tate MD, Pickett DL, van Rooijen N, Brooks AG, Reading PC (2010) Critical role of airway macrophages in modulating disease severity during influenza virus infection of mice. J Virol 84(15):7569–7580

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Tumpey TM, Garcia-Sastre A, Taubenberger JK, Palese P, Swayne DE, Pantin-Jackwood MJ et al (2005) Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol 79(23):14933–14944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Schneider C, Nobs SP, Heer AK, Kurrer M, Klinke G, van Rooijen N et al (2014) Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection. PLoS Pathog 10(4):e1004053

    Article  PubMed Central  PubMed  Google Scholar 

  29. Ghoneim HE, Thomas PG, McCullers JA (2013) Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J Immunol 191(3):1250–1259

    Article  CAS  PubMed  Google Scholar 

  30. Rahman I, MacNee W (2000) Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 16(3):534–554

    Article  CAS  PubMed  Google Scholar 

  31. Marti-Lliteras P, Regueiro V, Morey P, Hood DW, Saus C, Sauleda J, Agusti AG et al (2009) Nontypeable Haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke. Infect Immun 77(10):4232–4242

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Hodge S, Hodge G, Ahern J, Jersmann H, Holmes M, Reynolds PN (2007) Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 37(6):748–755

    Article  CAS  PubMed  Google Scholar 

  33. Hodge S, Matthews G, Mukaro V, Ahern J, Shivam A, Hodge G et al (2011) Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine. Am J Respir Cell Mol Biol 44(5):673–681

    Article  CAS  PubMed  Google Scholar 

  34. Pesci A, Balbi B, Majori M, Cacciani G, Bertacco S, Alciato P, Donner CF (1998) Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 12(2):380–386

    Article  CAS  PubMed  Google Scholar 

  35. Keatings VM, Collins PD, Scott DM, Barnes PJ (1996) Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153(2):530–534

    Article  CAS  PubMed  Google Scholar 

  36. Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P et al (1998) Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 158(4):1277–1285

    Article  PubMed  Google Scholar 

  37. Barnes PJ, Shapiro SD, Pauwels RA (2003) Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J 22(4):672–688

    Article  CAS  PubMed  Google Scholar 

  38. Finlay GA, O’Driscoll LR, Russell KJ, D’Arcy EM, Masterson JB, FitzGerald MX, O’Connor CM (1997) Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 156(1):240–247

    Article  CAS  PubMed  Google Scholar 

  39. Ohnishi K, Takagi M, Kurokawa Y, Satomi S, Konttinen YT (1998) Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 78(9):1077–1087

    CAS  PubMed  Google Scholar 

  40. Knapp S, Leemans JC, Florquin S, Branger J, Maris NA, Pater J et al (2003) Alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia. Am J Respir Crit Care Med 167(2):171–179

    Article  PubMed  Google Scholar 

  41. Cox G, Crossley J, Xing Z (1995) Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo. Am J Respir Cell Mol Biol 12(2):232–237

    Article  CAS  PubMed  Google Scholar 

  42. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 4:890–898

    Article  Google Scholar 

  43. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390(6658):350–351

    Article  CAS  PubMed  Google Scholar 

  44. Damiano VV, Tsang A, Kucich U, Abrams WR, Rosenbloom J, Kimbel P et al (1986) Immunolocalization of elastase in human emphysematous lungs. J Clin Invest 78(2):482–493

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Wynes MW, Frankel SK, Riches DW (2004) IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. J Leukoc Biol 76(5):1019–1027

    Article  CAS  PubMed  Google Scholar 

  46. Chetty A, Andersson S, Lassus P, Nielsen HC (2004) Insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) expression in human lung in RDS and BPD. Pediatr Pulmonol 37(2):128–136

    Article  PubMed  Google Scholar 

  47. Hung CF, Rohani MG, Lee SS, Chen P, Schnapp LM (2013) Role of IGF-1 pathway in lung fibroblast activation. Respir Res 14:102

    Article  PubMed Central  PubMed  Google Scholar 

  48. McQualter JL, Brouard N, Williams B, Baird BN, Sims-Lucas S, Yuen K et al (2009) Endogenous fibroblastic progenitor cells in the adult mouse lung are highly enriched in the sca-1 positive cell fraction. Stem Cells 27(3):623–633

    Article  CAS  PubMed  Google Scholar 

  49. McQualter JL, McCarty RC, Van der Velden J, O’Donoghue RJ, Asselin-Labat ML, Bozinovski S, Bertoncello I (2013) TGF-beta signaling in stromal cells acts upstream of FGF-10 to regulate epithelial stem cell growth in the adult lung. Stem Cell Res 11(3):1222–1233

    Article  CAS  PubMed  Google Scholar 

  50. McQualter JL, Yuen K, Williams B, Bertoncello I (2010) Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung. Proc Natl Acad Sci U S A 107(4):1414–1419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Morimoto K, Amano H, Sonoda F, Baba M, Senba M, Yoshimine H et al (2001) Alveolar macrophages that phagocytose apoptotic neutrophils produce hepatocyte growth factor during bacterial pneumonia in mice. Am J Respir Cell Mol Biol 24(5):608–615

    Article  CAS  PubMed  Google Scholar 

  52. Narasaraju T, Ng HH, Phoon MC, Chow VT (2010) MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. Am J Respir Cell Mol Biol 42(6):732–743

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Booth BW, Adler KB, Bonner JC, Tournier F, Martin LD (2001) Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha. Am J Respir Cell Mol Biol 25(6):739–743

    Article  CAS  PubMed  Google Scholar 

  54. Cakarova L, Marsh LM, Wilhelm J, Mayer K, Grimminger F, Seeger W et al (2009) Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med 180(6):521–532

    Article  CAS  PubMed  Google Scholar 

  55. Huffman Reed JA, Rice WR, Zsengeller ZK, Wert SE, Dranoff G, Whitsett JA (1997) GM-CSF enhances lung growth and causes alveolar type II epithelial cell hyperplasia in transgenic mice. Am J Physiol 273(4 Pt 1):L715–L725

    CAS  PubMed  Google Scholar 

  56. Paine R III, Wilcoxen SE, Morris SB, Sartori C, Baleeiro CE, Matthay MA, Christensen PJ (2003) Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury. Am J Pathol 163(6):2397–2406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Wynn TA, Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18(7):1028–1040

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Boorsma CE, Draijer C, Melgert BN (2013) Macrophage heterogeneity in respiratory diseases. Mediators Inflamm 2013:769214

    Article  PubMed Central  PubMed  Google Scholar 

  59. van Rijt LS, Jung S, Kleinjan A, Vos N, Willart M, Duez C et al (2005) In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med 201(6):981–991

    Article  PubMed Central  PubMed  Google Scholar 

  60. Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society, American College of Chest Physicians (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134(2):136–151

    Article  CAS  PubMed  Google Scholar 

  61. Mills CD, Ley K (2014) M1 and M2 Macrophages: the chicken and the egg of immunity. J Innate Immun 6(6):716–726

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686

    Article  CAS  PubMed  Google Scholar 

  63. Van Gorp H, Delputte PL, Nauwynck HJ (2010) Scavenger receptor CD163, a Jack-of-all-trades and potential target for cell-directed therapy. Mol Immunol 47(7–8):1650–1660

    Article  PubMed  Google Scholar 

  64. Kunz LI, Lapperre TS, Snoeck-Stroband JB, Budulac SE, Timens W, van Wijngaarden S et al (2011) Smoking status and anti-inflammatory macrophages in bronchoalveolar lavage and induced sputum in COPD. Respir Res 12:34

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Cortez VS, Robinette ML, Colonna M (2015) Innate lymphoid cells: new insights into function and development. Curr Opin Immunol 32C:71–77

    Article  Google Scholar 

  66. Diefenbach A, Colonna M, Koyasu S (2014) Development, differentiation, and diversity of innate lymphoid cells. Immunity 41(3):354–365

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Spits H, Di Santo JP (2011) The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 12(1):21–27

    Article  CAS  PubMed  Google Scholar 

  68. Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, McKenzie AN (2012) Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol 129(1):191–198

    Article  CAS  PubMed  Google Scholar 

  69. Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H (2012) IL-33-responsive lineage-CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol 188(3):1503–1513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Klein Wolterink RG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M, Levani Y, Hendriks RW (2012) Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol 42(5):1106–1116

    Article  PubMed  Google Scholar 

  71. Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA et al (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12(11):1045–1054

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Snyder JC, Zemke AC, Stripp BR (2009) Reparative capacity of airway epithelium impacts deposition and remodeling of extracellular matrix. Am J Respir Cell Mol Biol 40(6):633–642

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Byers DE, Alexander-Brett J, Patel AC, Agapov E, Dang-Vu G, Jin X et al (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 123(9):3967–3982

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Health Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia

    Jonathan L. McQualter, Ross Vlahos & Steven Bozinovski

  2. Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia

    Desiree Anthony

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  1. Jonathan L. McQualter
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  2. Desiree Anthony
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  3. Ross Vlahos
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  4. Steven Bozinovski
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Correspondence to Jonathan L. McQualter .

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Editors and Affiliations

  1. Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia

    Ivan Bertoncello

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McQualter, J.L., Anthony, D., Vlahos, R., Bozinovski, S. (2015). Immunomodulatory Regulation of Lung Regeneration and Repair. In: Bertoncello, I. (eds) Stem Cells in the Lung. Stem Cell Biology and Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-21082-7_10

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