Macrophages play an essential role in trauma-induced sterile inflammation and tissue repair

Review Article
First Online:
Received:
Accepted:
  • 5 Downloads

Abstract

Severe trauma is accompanied by a profound activation of the immune system. Patients with polytrauma develop systemic inflammatory response syndrome (SIRS) and often sepsis, which contributes substantially to high mortality of this condition. On a cellular level, necrosis and loss of plasma membrane integrity lead to the release of endogenous “damage-associated molecular patterns” (DAMPs) as danger signals, which in turn activate innate immune cells. Inflammation that occurs in the absence of invading pathogens has been termed sterile inflammation and trauma with tissue damage represents an acute form of sterile inflammation. Macrophages are a heterogeneous group of phagocytes of the innate immune system and serve as sentinels to detect loss of tissue integrity. Macrophages show a remarkable plasticity and undergo phenotypical changes in response to injury and repair. Under basal conditions, tissue-resident macrophages are distributed in various organ systems and have critical functions in tissue development and the maintenance of homeostasis. Inflammatory conditions, such as major trauma, lead to the rapid recruitment of blood-derived monocytes that mature into macrophages as well as direct recruitment of macrophages from the cavity that surrounds the injured organ. This leads to augmentation of the pool of tissue-resident macrophages. Besides their essential role in sensing tissue damage and initiating inflammation, macrophages contribution critically to tissue repair and wound healing, ultimately allowing full restoration. Dysregulated sterile inflammation and defective healing result in chronic inflammatory disease with persistent tissue damage. In this review, we summarize the cellular and molecular mechanisms that lead to activation of sterile inflammation, recruitment of immune cells and initiation of wound healing. We focus on the pivotal role of macrophages played in this context.

Keywords

Sterile inflammation Tissue-resident macrophages Cavity macrophages Repair 
This is a preview of subscription content, log in to check access

Notes

Acknowledgements

We would like to thank Servier for providing Servier Medical Art, which was used for the creation of figures. M.P. is supported by the German Research Foundation (DFG) with a Research Fellowship (PE 2737/1–1). P.K. is supported by grants from the Canadian Institute of Health Research (CIHR), Alberta Innovates Health Solutions (AIHS), the Heart and Stroke Foundation of Canada and the Canada Research Chairs programme.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

Ethical statement

This work is in compliance with all ethical standards. All procedures involving animal research were approved by the University of Calgary Animal Care Committee and were in compliance with Canadian Council for Animal Care Guidelines.

References

  1. 1.
    WHO. Injuries and Violence: the facts. Geneva: World Health Organization. 2014.Google Scholar
  2. 2.
    Haagsma JA, Graetz N, Bolliger I, Naghavi M, Higashi H, Mullany EC, et al. The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013. Inj Prev. 2016;22(1):3–18.  https://doi.org/10.1136/injuryprev-2015-041616.PubMedGoogle Scholar
  3. 3.
    Lord JM, Midwinter MJ, Chen Y-F, Belli A, Brohi K, Kovacs EJ, et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. The Lancet. 2014;384(9952):1455–65.  https://doi.org/10.1016/s0140-6736(14)60687-5.Google Scholar
  4. 4.
    Wafaisade A, Lefering R, Bouillon B, Sakka SG, Thamm OC, Paffrath T, et al. Epidemiology and risk factors of sepsis after multiple trauma: an analysis of 29,829 patients from the Trauma Registry of the German Society for Trauma Surgery. Crit Care Med. 2011;39(4):621–8.  https://doi.org/10.1097/CCM.0b013e318206d3df.PubMedGoogle Scholar
  5. 5.
    Lefering R, Paffrath T, Bouamra O, Coats TJ, Woodford M, Jenks T, et al. Epidemiology of in-hospital trauma deaths. Eur J Trauma Emerg Surg. 2012;38(1):3–9.  https://doi.org/10.1007/s00068-011-0168-4.PubMedGoogle Scholar
  6. 6.
    Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury. 2007;38(12):1336–45.  https://doi.org/10.1016/j.injury.2007.10.003.PubMedGoogle Scholar
  7. 7.
    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–55.PubMedGoogle Scholar
  8. 8.
    Angele MK, Faist E. Clinical review: immunodepression in the surgical patient and increased susceptibility to infection. Crit Care (London England). 2002;6(4):298–305.Google Scholar
  9. 9.
    Islam MN, Bradley BA, Ceredig R. Sterile post-traumatic immunosuppression. Clin Transl Immunol. 2016;5(4):e77.  https://doi.org/10.1038/cti.2016.13.Google Scholar
  10. 10.
    McDonald B, Kubes P. Innate immune cell trafficking and function during sterile inflammation of the liver. Gastroenterology. 2016;151(6):1087–95.  https://doi.org/10.1053/j.gastro.2016.09.048.PubMedGoogle Scholar
  11. 11.
    Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19(1):71–82.PubMedGoogle Scholar
  12. 12.
    Kaufmann SH. Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nat Immunol. 2008;9(7):705 – 12.  https://doi.org/10.1038/ni0708-705.PubMedGoogle Scholar
  13. 13.
    Gordon S. Elie Metchnikoff: father of natural immunity. Eur J Immunol. 2008;38(12):3257–64.  https://doi.org/10.1002/eji.200838855.PubMedGoogle Scholar
  14. 14.
    van Furth R, Cohn Z. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968;128:415 – 35.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Epelman S, Lavine KJ, Randolph GJ. Origin and functions of tissue macrophages. Immunity. 2014;41(1):21–35.  https://doi.org/10.1016/j.immuni.2014.06.013.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445 – 55.  https://doi.org/10.1038/nature12034.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14(6):392–404.  https://doi.org/10.1038/nri3671.PubMedGoogle Scholar
  18. 18.
    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–5.  https://doi.org/10.1126/science.1194637.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Bain CC, Bravo-Blas A, Scott CL, Perdiguero EG, Geissmann F, Henri S, et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014;15(10):929 – 37.  https://doi.org/10.1038/ni.2967.PubMedPubMedCentralGoogle Scholar
  20. 20.
    David BA, Rezende RM, Antunes MM, Santos MM, Freitas Lopes MA, Diniz AB, et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology. 2016;151(6):1176–91.  https://doi.org/10.1053/j.gastro.2016.08.024.PubMedGoogle Scholar
  21. 21.
    Kratofil RM, Kubes P, Deniset JF. Monocyte conversion during inflammation and injury. Arterioscler Thromb Vasc Biol. 2017;37(1):35–42.  https://doi.org/10.1161/ATVBAHA.116.308198.PubMedGoogle Scholar
  22. 22.
    Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14(10):986–95.  https://doi.org/10.1038/ni.2705.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723 – 37.  https://doi.org/10.1038/nri3073.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Bain CC, Jenkins SJ. The biology of serous cavity macrophages. Cellular immunology. 2018.  https://doi.org/10.1016/j.cellimm.2018.01.003.PubMedGoogle Scholar
  25. 25.
    Ghosn EE, Cassado AA, Govoni GR, Fukuhara T, Yang Y, Monack DM, et al. Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc Natl Acad Sci USA. 2010;107(6):2568–73.  https://doi.org/10.1073/pnas.0915000107.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen N, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science. 2011;332(6035):1284–8.  https://doi.org/10.1126/science.1204351.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Cassado Ados A, D’Imperio Lima MR, Bortoluci KR. Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. Front Immunol. 2015;6:225.  https://doi.org/10.3389/fimmu.2015.00225.PubMedGoogle Scholar
  28. 28.
    Bain CC, Hawley CA, Garner H, Scott CL, Schridde A, Steers NJ, et al. Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities. Nat Commun. 2016;7:ncomms11852.  https://doi.org/10.1038/ncomms11852.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Cain DW, O’Koren EG, Kan MJ, Womble M, Sempowski GD, Hopper K, et al. Identification of a tissue-specific, C/EBPbeta-dependent pathway of differentiation for murine peritoneal macrophages. J Immunol. 2013;191(9):4665–75.  https://doi.org/10.4049/jimmunol.1300581.PubMedGoogle Scholar
  30. 30.
    Rosas M, Davies LC, Giles PJ, Liao CT, Kharfan B, Stone TC, et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science. 2014;344(6184):645–8.  https://doi.org/10.1126/science.1251414.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Gautier EL, Ivanov S, Williams JW, Huang SC, Marcelin G, Fairfax K, et al. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J Exp Med. 2014;211(8):1525–31.  https://doi.org/10.1084/jem.20140570.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Okabe Y, Medzhitov R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014;157(4):832–44.  https://doi.org/10.1016/j.cell.2014.04.016.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Irvine KM, Banh X, Gadd VL, Wojcik KK, Ariffin JK, Jose S, et al. CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites. JCI insight. 2016;1(8):e86914.  https://doi.org/10.1172/jci.insight.86914.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, Niemietz P, et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology. 2015;62(1):279 – 91.  https://doi.org/10.1002/hep.27793.PubMedGoogle Scholar
  35. 35.
    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.  https://doi.org/10.1084/jem.20162152.PubMedCentralGoogle Scholar
  36. 36.
    Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164(12):6166–73.  https://doi.org/10.4049/jimmunol.164.12.6166.PubMedGoogle Scholar
  37. 37.
    Mills CD. M1 and M2 macrophages: oracles of health and disease. Critical reviews in immunology. 2012;32(6):463–88.PubMedGoogle Scholar
  38. 38.
    Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21.  https://doi.org/10.1038/nri.2017.11.PubMedGoogle Scholar
  39. 39.
    Mills CD. Anatomy of a discovery: m1 and m2 macrophages. Front Immunol. 2015;6:212.  https://doi.org/10.3389/fimmu.2015.00212.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20.  https://doi.org/10.1016/j.immuni.2014.06.008.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13(11):1118–28.  https://doi.org/10.1038/ni.2419.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.  https://doi.org/10.1016/j.immuni.2014.06.010.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Witmer-Pack MD, Hughes DA, Schuler G, Lawson L, McWilliam A, Inaba K, et al. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse. J Cell Sci. 1993;104(Pt 4):1021–9.PubMedGoogle Scholar
  44. 44.
    Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014;159(6):1327–40.  https://doi.org/10.1016/j.cell.2014.11.023.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006;18(1):39–48.  https://doi.org/10.1016/j.coi.2005.11.006.PubMedGoogle Scholar
  46. 46.
    Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9(4):259–70.  https://doi.org/10.1038/nri2528.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Erblich B, Zhu L, Etgen AM, Dobrenis K, Pollard JW. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PloS One. 2011;6(10):e26317.  https://doi.org/10.1371/journal.pone.0026317.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Chen GY, Nunez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826 – 37.  https://doi.org/10.1038/nri2873.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Shen H, Kreisel D, Goldstein DR. Processes of sterile inflammation. J Immunol. 2013;191(6):2857–63.  https://doi.org/10.4049/jimmunol.1301539.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Zhang X, Mosser DM. Macrophage activation by endogenous danger signals. J Pathol. 2008;214(2):161–78.  https://doi.org/10.1002/path.2284.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu Rev Immunol. 2010;28:321 – 42.  https://doi.org/10.1146/annurev-immunol-030409-101311.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat Immunol. 2018;19(4):327 – 41.  https://doi.org/10.1038/s41590-018-0064-8.PubMedGoogle Scholar
  53. 53.
    Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunological reviews. 2007;220:60–81.  https://doi.org/10.1111/j.1600-065X.2007.00579.x.PubMedGoogle Scholar
  54. 54.
    Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3(6):920–40.  https://doi.org/10.3390/v3060920.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Hernandez C, Huebener P, Schwabe RF. Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene. 2016;35(46):5931–41.  https://doi.org/10.1038/onc.2016.104.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Venereau E, Ceriotti C, Bianchi ME. DAMPs from cell death to new life. Front Immunol. 2015;6:422.  https://doi.org/10.3389/fimmu.2015.00422.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.  https://doi.org/10.1038/nature08780.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Quintana FJ, Cohen IR. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J Immunol. 2005;175(5):2777–82.PubMedGoogle Scholar
  59. 59.
    Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC. Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacology therapeutics. 2006;112(2):358–404.  https://doi.org/10.1016/j.pharmthera.2005.04.013.PubMedGoogle Scholar
  60. 60.
    Kono H, Chen CJ, Ontiveros F, Rock KL. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest. 2010;120(6):1939–49.  https://doi.org/10.1172/jci40124.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Yang D, Oyaizu Y, Oyaizu H, Olsen GJ, Woese CR. Mitochondrial. origins. Proc Natl Acad Sci USA. 1985;82(13):4443–7.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–72.  https://doi.org/10.1053/j.gastro.2012.09.008.PubMedGoogle Scholar
  63. 63.
    Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci USA. 2009;106(48):20388–93.  https://doi.org/10.1073/pnas.0908698106.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.  https://doi.org/10.1038/ni.1980.PubMedGoogle Scholar
  65. 65.
    Stros M. HMGB proteins: interactions with DNA and chromatin. Biochimica et Biophysica Acta. 2010;1799(1–2):101 – 13.  https://doi.org/10.1016/j.bbagrm.2009.09.008.PubMedGoogle Scholar
  66. 66.
    Yang H, Rivera Z, Jube S, Nasu M, Bertino P, Goparaju C, et al. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc Natl Acad Sci USA. 2010;107(28):12611–6.  https://doi.org/10.1073/pnas.1006542107.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Wu H, Ma J, Wang P, Corpuz TM, Panchapakesan U, Wyburn KR, et al. HMGB1 contributes to kidney ischemia reperfusion injury. J Am Soc Nephrol: JASN. 2010;21(11):1878–90.  https://doi.org/10.1681/asn.2009101048.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Yohe HC, O’Hara KA, Hunt JA, Kitzmiller TJ, Wood SG, Bement JL, et al. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity. Am J Physiol Gastrointestinal Liver Physiol. 2006;290(6):G1269-79.  https://doi.org/10.1152/ajpgi.00239.2005.Google Scholar
  69. 69.
    Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, et al. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol. 2005;175(11):7661–8.PubMedGoogle Scholar
  70. 70.
    Shen XD, Ke B, Zhai Y, Gao F, Busuttil RW, Cheng G, et al. Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia/reperfusion injury. Am J Transplant. 2005;5(8):1793–800.  https://doi.org/10.1111/j.1600-6143.2005.00932.x.PubMedGoogle Scholar
  71. 71.
    Coddou C, Yan Z, Obsil T, Huidobro-Toro JP, Stojilkovic SS. Activation and regulation of purinergic P2X receptor channels. Pharmacol Rev. 2011;63(3):641 – 83.  https://doi.org/10.1124/pr.110.003129.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol. 2008;8(4):279–89.  https://doi.org/10.1038/nri2215.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Haruma J, Teshigawara K, Hishikawa T, Wang D, Liu K, Wake H, et al. Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats. Sci Rep. 2016;6:37755.  https://doi.org/10.1038/srep37755.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Liu A, Fang H, Dirsch O, Jin H, Dahmen U. Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion. PloS One. 2012;7(4):e35379.  https://doi.org/10.1371/journal.pone.0035379.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–9.  https://doi.org/10.1038/nm1315.PubMedGoogle Scholar
  76. 76.
    Liew FY, Xu D, Brint EK, O’Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5(6):446–58.  https://doi.org/10.1038/nri1630.PubMedGoogle Scholar
  77. 77.
    Miyake K, Shibata T, Ohto U, Shimizu T, Saitoh SI, Fukui R, et al. Mechanisms controlling nucleic-acid-sensing Toll-like receptors. Int Immunol. 2018.  https://doi.org/10.1093/intimm/dxy016.PubMedGoogle Scholar
  78. 78.
    Brentano F, Kyburz D, Schorr O, Gay R, Gay S. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol. 2005;233(2):90 – 6.  https://doi.org/10.1016/j.cellimm.2005.04.018.PubMedGoogle Scholar
  79. 79.
    Hoth JJ, Hudson WP, Brownlee NA, Yoza BK, Hiltbold EM, Meredith JW, et al. Toll-like receptor 2 participates in the response to lung injury in a murine model of pulmonary contusion. Shock (Augusta Ga). 2007;28(4):447–52.  https://doi.org/10.1097/shk.0b013e318048801a.Google Scholar
  80. 80.
    DeMaria EJ, Pellicane JV, Lee RB. Hemorrhagic shock in endotoxin-resistant mice: improved survival unrelated to deficient production of tumor necrosis factor. J Trauma. 1993;35(5):720–4 (discussion 4–5).PubMedGoogle Scholar
  81. 81.
    Gill R, Ruan X, Menzel CL, Namkoong S, Loughran P, Hackam DJ, et al. Systemic inflammation and liver injury following hemorrhagic shock and peripheral tissue trauma involve functional TLR9 signaling on bone marrow-derived cells and parenchymal cells. Shock (Augusta Ga). 2011;35(2):164–70.  https://doi.org/10.1097/SHK.0b013e3181eddcab.Google Scholar
  82. 82.
    Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016;16(7):407–20.  https://doi.org/10.1038/nri.2016.58.PubMedGoogle Scholar
  83. 83.
    Menzel CL, Sun Q, Loughran PA, Pape HC, Billiar TR, Scott MJ. Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation. Mol Med. 2011;17(9–10):1031–8.  https://doi.org/10.2119/molmed.2011.00015.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Wu J, Yan Z, Schwartz DE, Yu J, Malik AB, Hu G. Activation of NLRP3 inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury. J Immunol. 2013;190(7):3590–9.  https://doi.org/10.4049/jimmunol.1200860.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Kuipers MT, Aslami H, Janczy JR, van der Sluijs KF, Vlaar AP, Wolthuis EK, et al. Ventilator-induced lung injury is mediated by the NLRP3 inflammasome. Anesthesiology. 2012;116(5):1104–15.  https://doi.org/10.1097/ALN.0b013e3182518bc0.PubMedGoogle Scholar
  86. 86.
    Timmermans K, Kox M, Vaneker M, van den Berg M, John A, van Laarhoven A, et al. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive Care Med. 2016;42(4):551–61.  https://doi.org/10.1007/s00134-015-4205-3.PubMedPubMedCentralGoogle Scholar
  87. 87.
    McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330(6002):362–6.  https://doi.org/10.1126/science.1195491.PubMedGoogle Scholar
  88. 88.
    Wang J, Hossain M, Thanabalasuriar A, Gunzer M, Meininger C, Kubes P. Visualizing the function and fate of neutrophils in sterile injury and repair. Science. 2017;358(6359):111–6.  https://doi.org/10.1126/science.aam9690.PubMedGoogle Scholar
  89. 89.
    Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656 – 61.  https://doi.org/10.1126/science.1178331.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Kono H, Karmarkar D, Iwakura Y, Rock KL. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J Immunol. 2010;184(8):4470–8.  https://doi.org/10.4049/jimmunol.0902485.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 2010;30(3):245 – 57.  https://doi.org/10.1055/s-0030-1255354.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Peiser L, Mukhopadhyay S, Gordon S. Scavenger receptors in innate immunity. Curr Opin Immunol. 2002;14(1):123–8.PubMedGoogle Scholar
  93. 93.
    Stables MJ, Shah S, Camon EB, Lovering RC, Newson J, Bystrom J, et al. Transcriptomic analyses of murine resolution-phase macrophages. Blood. 2011;118(26):e192-208.  https://doi.org/10.1182/blood-2011-04-345330.PubMedGoogle Scholar
  94. 94.
    DiPietro LA. Wound healing: the role of the macrophage and other immune cells. Shock (Augusta Ga). 1995;4(4):233–40.Google Scholar
  95. 95.
    Wynn TA, Vannella KM. Macrophages in Tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450–62.  https://doi.org/10.1016/j.immuni.2016.02.015.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992;3(2):211 – 20.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Chujo S, Shirasaki F, Kondo-Miyazaki M, Ikawa Y, Takehara K. Role of connective tissue growth factor and its interaction with basic fibroblast growth factor and macrophage chemoattractant protein-1 in skin fibrosis. J Cell Physiol. 2009;220(1):189–95.  https://doi.org/10.1002/jcp.21750.PubMedGoogle Scholar
  98. 98.
    Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120(3):613–25.  https://doi.org/10.1182/blood-2012-01-403386.PubMedGoogle Scholar
  99. 99.
    Rappolee DA, Mark D, Banda MJ, Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science (New York, NY). 1988;241(4866):708–12.Google Scholar
  100. 100.
    Shimokado K, Raines EW, Madtes DK, Barrett TB, Benditt EP, Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985;43(1):277–86.PubMedGoogle Scholar
  101. 101.
    Stables MJ, Gilroy DW. Old and new generation lipid mediators in acute inflammation and resolution. Progress Lipid Res. 2011;50(1):35–51.  https://doi.org/10.1016/j.plipres.2010.07.005.Google Scholar
  102. 102.
    Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16(4):452–9.  https://doi.org/10.1038/nm.2106.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Shouval DS, Biswas A, Goettel JA, McCann K, Conaway E, Redhu NS, et al. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity. 2014;40(5):706 – 19.  https://doi.org/10.1016/j.immuni.2014.03.011.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S, Kim KW, et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity. 2014;40(5):720 – 33.  https://doi.org/10.1016/j.immuni.2014.03.012.PubMedGoogle Scholar
  105. 105.
    Landen NX, Li D, Stahle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci. 2016;73(20):3861–85.  https://doi.org/10.1007/s00018-016-2268-0.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8(12):958 – 69.  https://doi.org/10.1038/nri2448.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18(7):1028–40.  https://doi.org/10.1038/nm.2807.PubMedPubMedCentralGoogle Scholar
  108. 108.
    London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung S, et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J Exp Med. 2011;208(1):23–39.  https://doi.org/10.1084/jem.20101202.PubMedPubMedCentralGoogle Scholar
  109. 109.
    van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol. 2007;170(3):818–29.  https://doi.org/10.2353/ajpath.2007.060547.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Zhang MZ, Yao B, Yang S, Jiang L, Wang S, Fan X, et al. CSF-1 signaling mediates recovery from acute kidney injury. J Clin Invest. 2012;122(12):4519–32.  https://doi.org/10.1172/jci60363.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115(1):56–65.  https://doi.org/10.1172/JCI22675.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010;184(7):3964–77.  https://doi.org/10.4049/jimmunol.0903356.PubMedGoogle Scholar
  113. 113.
    Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 2014;40(1):91–104.  https://doi.org/10.1016/j.immuni.2013.11.019.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Lavine KJ, Epelman S, Uchida K, Weber KJ, Nichols CG, Schilling JD, et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci USA. 2014;111(45):16029–34.  https://doi.org/10.1073/pnas.1406508111.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Chan CT, Moore JP, Budzyn K, Guida E, Diep H, Vinh A et al. Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension (Dallas: 1979). 2012;60(5):1207–12.  https://doi.org/10.1161/hypertensionaha.112.201251.Google Scholar
  116. 116.
    Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 2009;6(7):e1000113.  https://doi.org/10.1371/journal.pmed.1000113.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Hsieh CL, Niemi EC, Wang SH, Lee CC, Bingham D, Zhang J, et al. CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury. J Neurotrauma. 2014;31(20):1677–88.  https://doi.org/10.1089/neu.2013.3252.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Morganti JM, Jopson TD, Liu S, Riparip LK, Guandique CK, Gupta N, et al. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J Neurosci. 2015;35(2):748 – 60.  https://doi.org/10.1523/jneurosci.2405-14.2015.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Minutti CM, Knipper JA, Allen JE, Zaiss DM. Tissue-specific contribution of macrophages to wound healing. Semin Cell Dev Biol. 2017;61:3–11.  https://doi.org/10.1016/j.semcdb.2016.08.006.PubMedGoogle Scholar
  120. 120.
    Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18(4):572–9.  https://doi.org/10.1038/nm.2667.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr1 + monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology. 2009;50(1):261 – 74.  https://doi.org/10.1002/hep.22950.PubMedGoogle Scholar
  122. 122.
    Kassel KM, Guo GL, Tawfik O, Luyendyk JP. Monocyte chemoattractant protein-1 deficiency does not affect steatosis or inflammation in livers of mice fed a methionine-choline-deficient diet. Lab Investig J Technical Methods Pathol. 2010;90(12):1794 – 804.  https://doi.org/10.1038/labinvest.2010.143.Google Scholar
  123. 123.
    Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology. 2016;64(5):1667–82.  https://doi.org/10.1002/hep.28682.PubMedGoogle Scholar
  124. 124.
    Dal-Secco D, Wang J, Zeng Z, Kolaczkowska E, Wong CH, Petri B, et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J Exp Med. 2015;212(4):447–56.  https://doi.org/10.1084/jem.20141539.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Liew PX, Lee WY, Kubes P. iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity. 2017;47(4):752–65 e5.  https://doi.org/10.1016/j.immuni.2017.09.016.PubMedGoogle Scholar
  126. 126.
    Brennan PJ, Brigl M, Brenner MB. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol. 2013;13(2):101–17.  https://doi.org/10.1038/nri3369.PubMedGoogle Scholar
  127. 127.
    Tupin E, Kinjo Y, Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol. 2007;5(6):405–17.  https://doi.org/10.1038/nrmicro1657.PubMedGoogle Scholar
  128. 128.
    Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol. 2007;25:297–336.  https://doi.org/10.1146/annurev.immunol.25.022106.141711.PubMedGoogle Scholar
  129. 129.
    Lee WY, Moriarty TJ, Wong CH, Zhou H, Strieter RM, van Rooijen N, et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat Immunol. 2010;11(4):295–302.  https://doi.org/10.1038/ni.1855.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Wang J, Kubes P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell. 2016;165(3):668 – 78.  https://doi.org/10.1016/j.cell.2016.03.009.PubMedGoogle Scholar
  131. 131.
    Browder W, Williams D, Pretus H, Olivero G, Enrichens F, Mao P, et al. Beneficial effect of enhanced macrophage function in the trauma patient. Annals of surgery. 1990;211(5):605 – 12 (discussion 12–3).PubMedPubMedCentralGoogle Scholar
  132. 132.
    Stahel PF, Smith WR, Moore EE. Role of biological modifiers regulating the immune response after trauma. Injury. 2007;38(12):1409–22.  https://doi.org/10.1016/j.injury.2007.09.023.PubMedGoogle Scholar
  133. 133.
    Novak ML, Weinheimer-Haus EM, Koh TJ. Macrophage activation and skeletal muscle healing following traumatic injury. J Pathol. 2014;232(3):344–55.  https://doi.org/10.1002/path.4301.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology. 2011;53(6):2003–15.  https://doi.org/10.1002/hep.24315.PubMedGoogle Scholar
  135. 135.
    Suzuki T, Arumugam P, Sakagami T, Lachmann N, Chalk C, Sallese A, et al. Pulmonary macrophage transplantation therapy. Nature. 2014;514(7523):450–4.  https://doi.org/10.1038/nature13807.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Cao Q, Wang C, Zheng D, Wang Y, Lee VW, Wang YM, et al. IL-25 induces M2 macrophages and reduces renal injury in proteinuric kidney disease. J Am Soc Nephrol: JASN. 2011;22(7):1229–39.  https://doi.org/10.1681/asn.2010070693.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Stutchfield BM, Antoine DJ, Mackinnon AC, Gow DJ, Bain CC, Hawley CA, et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology. 2015;149(7):1896–909.e14.  https://doi.org/10.1053/j.gastro.2015.08.053.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Ruseva MM, Ramaglia V, Morgan BP, Harris CL. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proc Natl Acad Sci USA. 2015;112(46):14319–24.  https://doi.org/10.1073/pnas.1513698112.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Li Z, Wu X, Wu X, Yu J, Yuan Q, Du Z, et al. Admission circulating monocytes level is an independent predictor of outcome in traumatic brain injury. Brain Injury. 2018;32(4):515 – 22.  https://doi.org/10.1080/02699052.2018.1429023.PubMedGoogle Scholar
  140. 140.
    Lam SW, Leenen LP, van Solinge WW, Hietbrink F, Huisman A. Comparison between the prognostic value of the white blood cell differential count and morphological parameters of neutrophils and lymphocytes in severely injured patients for 7-day in-hospital mortality. Biomark: Biochem Indicat Exposure, Response, Suscept Chem. 2012;17(7):642–7.  https://doi.org/10.3109/1354750x.2012.712161.Google Scholar
  141. 141.
    Haupt W, Riese J, Mehler C, Weber K, Zowe M, Hohenberger W. Monocyte function before and after surgical trauma. Dig Surg. 1998;15(2):102–4.  https://doi.org/10.1159/000018601.PubMedGoogle Scholar
  142. 142.
    Kaito M, Araya S, Gondo Y, Fujita M, Minato N, Nakanishi M, et al. Relevance of distinct monocyte subsets to clinical course of ischemic stroke patients. PloS one. 2013;8(8):e69409.  https://doi.org/10.1371/journal.pone.0069409.PubMedPubMedCentralGoogle Scholar
  143. 143.
    West SD, Goldberg D, Ziegler A, Krencicki M, Du Clos TW, Mold C. Transforming growth factor-β, macrophage colony-stimulating factor and C-reactive protein levels Correlate with CD14 high CD16+ monocyte induction and activation in trauma patients. PloS One. 2012;7(12):e52406.  https://doi.org/10.1371/journal.pone.0052406.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Daghestani HN, Pieper CF, Kraus VB. (Hoboken. Soluble macrophage biomarkers indicate inflammatory phenotypes in patients with knee osteoarthritis. Arthritis Rheumatol (Hoboken, NJ). 2015;67(4):956–65.  https://doi.org/10.1002/art.39006.Google Scholar
  145. 145.
    Zhang B, Cao M, He Y, Liu Y, Zhang G, Yang C, et al. Increased circulating M2-like monocytes in patients with breast cancer. Tumour Biol J Int Soc Oncodev Biol Med. 2017;39(6):1010428317711571.  https://doi.org/10.1177/1010428317711571.Google Scholar
  146. 146.
    Xie WJ, Yu HQ, Zhang Y, Liu Q, Meng HM. CD163 promotes hematoma absorption and improves neurological functions in patients with intracerebral hemorrhage. Neural Regener Res. 2016;11(7):1122–7.  https://doi.org/10.4103/1673-5374.187047.Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and PhysiologyUniversity of CalgaryCalgaryCanada
  2. 2.Snyder Institute for Chronic Diseases, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
  3. 3.I. Department of MedicineUniversity Medical Centre Hamburg-Eppendorf, University of HamburgHamburgGermany

Personalised recommendations