Review Article | Published:

Innate immune responses to trauma

Nature Immunologyvolume 19pages327341 (2018) | Download Citation

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Abstract

Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.

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References

  1. 1.

    Lord, J. M. et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet 384, 1455–1465 (2014).

  2. 2.

    Sauaia, A., Moore, F. A. & Moore, E. E. Postinjury inflammation and organ dysfunction. Crit. Care Clin. 33, 167–191 (2017).

  3. 3.

    Mira, J. C. et al. The epidemiology of chronic critical illness after severe traumatic injury at two level-one trauma centers. Crit. Care Med. 45, 1989–1996 (2017).

  4. 4.

    Gabbe, B. J. et al. Long-term health status and trajectories of seriously injured patients: a population-based longitudinal study. PLoS Med. 14, e1002322 (2017).

  5. 5.

    Callcut, R. A. et al. Discovering the truth about life after discharge: Long-term trauma-related mortality. J. Trauma Acute Care Surg. 80, 210–217 (2016).

  6. 6.

    Keel, M. & Trentz, O. Pathophysiology of polytrauma. Injury 36, 691–709 (2005).

  7. 7.

    Adib-Conquy, M. & Cavaillon, J. M. Compensatory anti-inflammatory response syndrome. Thromb. Haemost. 101, 36–47 (2009).

  8. 8.

    Cabrera, C. P. et al. Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: A prospective cohort study. PLoS Med. 14, e1002352 (2017).

  9. 9.

    Dijkink, S. et al. Polytrauma patients in the Netherlands and the USA: A bi-institutional comparison of processes and outcomes of care. Injury 49, 104–109 (2018).

  10. 10.

    Minei, J. P. et al. The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock. Crit. Care Med. 40, 1129–1135 (2012).

  11. 11.

    Billiar, T. R. & Vodovotz, Y. Time for trauma immunology. PLoS Med. 14, e1002342 (2017).

  12. 12.

    Netea, M. G. et al. A guiding map for inflammation. Nat. Immunol. 18, 826–831 (2017).

  13. 13.

    Zhao, H., Kilgas, S., Alam, A., Eguchi, S. & Ma, D. The role of extracellular adenosine triphosphate in ischemic organ injury. Crit. Care Med. 44, 1000–1012 (2016).

  14. 14.

    Gebhard, F. & Huber-Lang, M. Polytrauma–pathophysiology and management principles. Langenbecks Arch. Surg. 393, 825–831 (2008).

  15. 15.

    Qiang, X. et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat. Med 19, 1489–1495 (2013).

  16. 16.

    Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

  17. 17.

    Davis, G. E., Bayless, K. J., Davis, M. J. & Meininger, G. A. Regulation of tissue injury responses by the exposure of matricryptic sites within extracellular matrix molecules. Am. J. Pathol. 156, 1489–1498 (2000).

  18. 18.

    Burk, A. M. et al. Early complementopathy after multiple injuries in humans. Shock 37, 348–354 (2012).

  19. 19.

    Ganter, M. T. et al. Role of the alternative pathway in the early complement activation following major trauma. Shock 28, 29–34 (2007).

  20. 20.

    Kenawy, H. I., Boral, I. & Bevington, A. complement-coagulation cross-talk: a potential mediator of the physiological activation of complement by low pH. Front. Immunol. 6, 215 (2015).

  21. 21.

    Cekic, C. & Linden, J. Purinergic regulation of the immune system. Nat. Rev. Immunol. 16, 177–192 (2016).

  22. 22.

    Xiao, W. et al. A genomic storm in critically injured humans. J. Exp. Med. 208, 2581–2590 (2011).

  23. 23.

    Lederer, J. A. et al. Comparison of longitudinal leukocyte gene expression after burn injury or trauma-hemorrhage in mice. Physiol. Genomics 32, 299–310 (2008).

  24. 24.

    Seshadri, A. et al. Phenotyping the immune response to trauma: a multiparametric systems immunology approach. Crit. Care Med. 45, 1523–1530 (2017).

  25. 25.

    Munford, R. S. & Pugin, J. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am. J. Respir. Crit. Care Med. 163, 316–321 (2001).

  26. 26.

    Hazeldine, J. et al. Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: A prospective cohort study. PLoS Med. 14, e1002338 (2017).

  27. 27.

    Itagaki, K. et al. Mitochondrial DNA released by trauma induces neutrophil extracellular traps. PLoS One 10, e0120549 (2015).

  28. 28.

    Timmermans, K. et al. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive Care Med. 42, 551–561 (2016).

  29. 29.

    Mitchell, T. A. et al. Traumatic hemothorax blood contains elevated levels of microparticles that are prothrombotic but inhibit platelet aggregation. Shock 47, 680–687 (2017).

  30. 30.

    Matijevic, N. et al. Microvesicle phenotypes are associated with transfusion requirements and mortality in subjects with severe injuries. J. Extracell. Vesicles 4, 29338 (2015).

  31. 31.

    Németh, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42–49 (2009).

  32. 32.

    Jones, H. R., Robb, C. T., Perretti, M. & Rossi, A. G. The role of neutrophils in inflammation resolution. Semin. Immunol. 28, 137–145 (2016).

  33. 33.

    Frith, D. et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J. Thromb. Haemost. 8, 1919–1925 (2010).

  34. 34.

    Bastian, O. W. et al. Impaired bone healing in multitrauma patients is associated with altered leukocyte kinetics after major trauma. J. Inflamm. Res. 9, 69–78 (2016).

  35. 35.

    Chen, W. et al. Cytokine cascades induced by mechanical trauma injury alter voltage-gated sodium channel activity in intact cortical neurons. J. Neuroinflammation 14, 73 (2017).

  36. 36.

    Jorgensen, I., Rayamajhi, M. & Miao, E. A. Programmed cell death as a defence against infection. Nat. Rev. Immunol. 17, 151–164 (2017).

  37. 37.

    Paunel-Görgülü, A., Kirichevska, T., Lögters, T., Windolf, J. & Flohé, S. Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis. Mol. Med. 18, 325–335 (2012).

  38. 38.

    Hotchkiss, R. S. et al. Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patients with trauma and shock. Crit. Care Med. 28, 3207–3217 (2000).

  39. 39.

    Heffernan, D. S. et al. Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit. Care 16, R12 (2012).

  40. 40.

    Kottke, M. A. & Walters, T. J. Where’s the leak in vascular barriers? a review. Shock 46, 20–36 (2016).

  41. 41.

    Gentile, L. F. et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J. Trauma Acute Care Surg. 72, 1491–1501 (2012).

  42. 42.

    Hietbrink, F., Koenderman, L., van Wessem, K. J. & Leenen, L. P. The impact of intramedullary nailing of tibia fractures on the innate immune system. Shock 44, 209–214 (2015).

  43. 43.

    Kanakaris, N. K., Anthony, C., Papasotiriou, A. & Giannoudis, P. V. Inflammatory response after nailing. Injury 48, S10–S14 (2017).

  44. 44.

    Pape, H. C. et al. Impact of intramedullary instrumentation versus damage control for femoral fractures on immunoinflammatory parameters: prospective randomized analysis by the EPOFF Study Group. J. Trauma 55, 7–13 (2003).

  45. 45.

    Pape, H. C. et al. Impact of the method of initial stabilization for femoral shaft fractures in patients with multiple injuries at risk for complications (borderline patients). Ann. Surg. 246, 491–499 (2007).

  46. 46.

    Rixen, D. et al. Randomized, controlled, two-arm, interventional, multicenter study on risk-adapted damage control orthopedic surgery of femur shaft fractures in multiple-trauma patients. Trials 17, 47 (2016).

  47. 47.

    Giannoudis, P. V., Giannoudis, V. P. & Horwitz, D. S. Time to think outside the box: ‘prompt-individualised-safe management’ (PR.I.S.M.) should prevail in patients with multiple injuries. Injury 48, 1279–1282 (2017).

  48. 48.

    Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101, 3765–3777 (2003).

  49. 49.

    Tracey, K. J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).

  50. 50.

    Johansson, P. I. et al. Traumatic endotheliopathy: a prospective observational study of 424 severely injured patients. Ann. Surg. 265, 597–603 (2017).

  51. 51.

    Ekdahl, K. N. et al. Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunol. Rev. 274, 245–269 (2016).

  52. 52.

    Lissauer, M. E. et al. Coagulation and complement protein differences between septic and uninfected systemic inflammatory response syndrome patients. J. Trauma 62, 1082–1092 (2007).

  53. 53.

    Muroya, T. et al. C4d deposits on the surface of RBCs in trauma patients and interferes with their function. Crit. Care Med. 42, e364–e372 (2014).

  54. 54.

    Kambas, K. et al. C5a and TNF-α up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J. Immunol. 180, 7368–7375 (2008).

  55. 55.

    Kral, J. B., Schrottmaier, W. C., Salzmann, M. SpringerAmpamp; Assinger, A. Platelet interaction with innate immune cells. Transfus. Med. Hemother. 43, 78–88 (2016).

  56. 56.

    Sun, S. et al. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS One 8, e59989 (2013).

  57. 57.

    Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).

  58. 58.

    Jorch, S. K. & Kubes, P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat. Med. 23, 279–287 (2017).

  59. 59.

    Rittirsch, D. et al. An integrated clinico-transcriptomic approach identifies a central role of the heme degradation pathway for septic complications after trauma. Ann. Surg. 264, 1125–1134 (2016).

  60. 60.

    Deitch, E. A. et al. Trauma-hemorrhagic shock induces a CD36-dependent RBC endothelial-adhesive phenotype. Crit. Care Med. 42, e200–e210 (2014).

  61. 61.

    Maegele, M., Schöchl, H. & Cohen, M. J. An update on the coagulopathy of trauma. Shock 41, 21–25 (2014).

  62. 62.

    Naumann, D.N. et al. Endotheliopathy of trauma is an on-scene phenomenon, and is associated with multiple organ dysfunction syndrome: a prospective observational study. Shock (2017).

  63. 63.

    Denk, S. et al. Early detection of junctional adhesion molecule-1 (JAM-1) in the circulation after experimental and clinical polytrauma. Mediators Inflamm. 2015, 463950 (2015).

  64. 64.

    Johansson, P. I., Stensballe, J., Rasmussen, L. S. & Ostrowski, S. R. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann. Surg. 254, 194–200 (2011).

  65. 65.

    Denk, S. et al. Role of hemorrhagic shock in experimental polytrauma. Shock 49, 154–163 (2018).

  66. 66.

    Halbgebauer, R. et al. Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma. J. Crit. Care 44, 229–237 (2017).

  67. 67.

    White, N. J., Ward, K. R., Pati, S., Strandenes, G. & Cap, A. P. Hemorrhagic blood failure: oxygen debt, coagulopathy, and endothelial damage. J. Trauma Acute Care Surg. 82, S41–S49 (2017).

  68. 68.

    Ostrowski, S. R. & Johansson, P. I. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J. Trauma Acute Care Surg. 73, 60–66 (2012).

  69. 69.

    Nelson, A., Berkestedt, I., Schmidtchen, A., Ljunggren, L. & Bodelsson, M. Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma. Shock 30, 623–627 (2008).

  70. 70.

    Denk, S. et al. Complement C5a functions as a master switch for the ph balance in neutrophils exerting fundamental immunometabolic effects. J. Immunol. 198, 4846–4854 (2017).

  71. 71.

    Cheng, S. C. et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406–413 (2016).

  72. 72.

    Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

  73. 73.

    van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P. & Netea, M. G. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol. 17, 407–420 (2017).

  74. 74.

    Pfeifer, R., Heussen, N., Michalewicz, E., Hilgers, R. D. & Pape, H. C. Incidence of adult respiratory distress syndrome in trauma patients: a systematic review and meta-analysis over a period of three decades. J. Trauma Acute Care Surg 83, 496–506 (2017).

  75. 75.

    Hoth, J. J., Wells, J. D., Jones, S. E., Yoza, B. K. & McCall, C. E. Complement mediates a primed inflammatory response after traumatic lung injury. J. Trauma Acute Care Surg. 76, 601–608 (2014).

  76. 76.

    Schmidt, E. P. et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat. Med 18, 1217–1223 (2012).

  77. 77.

    Niesler, U., Palmer, A., Radermacher, P. & Huber-Lang, M. S. Role of alveolar macrophages in the inflammatory response after trauma. Shock 42, 3–10 (2014).

  78. 78.

    Grommes, J. & Soehnlein, O. Contribution of neutrophils to acute lung injury. Mol. Med. 17, 293–307 (2011).

  79. 79.

    Robb, C. T., Regan, K. H., Dorward, D. A. & Rossi, A. G. Key mechanisms governing resolution of lung inflammation. Semin. Immunopathol. 38, 425–448 (2016).

  80. 80.

    Herold, S., Mayer, K. & Lohmeyer, J. Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair. Front. Immunol. 2, 65 (2011).

  81. 81.

    Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11, 1173–1179 (2005).

  82. 82.

    Wen, Z. et al. Neutrophils counteract autophagy-mediated anti-inflammatory mechanisms in alveolar macrophage: role in posthemorrhagic shock acute lung inflammation. J. Immunol. 193, 4623–4633 (2014).

  83. 83.

    Westphalen, K. et al. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature 506, 503–506 (2014).

  84. 84.

    Koeppen, M. et al. Detrimental role of the airway mucin Muc5ac during ventilator-induced lung injury. Mucosal Immunol 6, 762–775 (2013).

  85. 85.

    Whitsett, J. A. & Alenghat, T. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat. Immunol. 16, 27–35 (2015).

  86. 86.

    Raghavendran, K. et al. Lung contusion: inflammatory mechanisms and interaction with other injuries. Shock 32, 122–130 (2009).

  87. 87.

    Aufmkolk, M. et al. Local effect of lung contusion on lung surfactant composition in multiple trauma patients. Crit. Care Med. 27, 1441–1446 (1999).

  88. 88.

    Hoth, J. J., Wells, J. D., Yoza, B. K. & McCall, C. E. Innate immune response to pulmonary contusion: identification of cell type-specific inflammatory responses. Shock 37, 385–391 (2012).

  89. 89.

    Islam, M. N. et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 18, 759–765 (2012).

  90. 90.

    Hüsecken, Y. et al. MDSCs are induced after experimental blunt chest trauma and subsequently alter antigen-specific T cell responses. Sci. Rep. 7, 12808 (2017).

  91. 91.

    Liew, F. Y., Girard, J. P. & Turnquist, H. R. Interleukin-33 in health and disease. Nat. Rev. Immunol. 16, 676–689 (2016).

  92. 92.

    Xu, J. et al. IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model. PLoS Med. 14, e1002365 (2017).

  93. 93.

    Zhao, C. et al. Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses. J. Trauma Acute Care Surg. 76, 1222–1227 (2014).

  94. 94.

    Li, H. et al. Mitochondrial damage-associated molecular patterns from fractures suppress pulmonary immune responses via formyl peptide receptors 1 and 2. J. Trauma Acute Care Surg. 78, 272–279 (2015).

  95. 95.

    Kojima, M. et al. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4. FASEB J. 32, 97–110 (2018).

  96. 96.

    Langness, S., Costantini, T. W., Morishita, K., Eliceiri, B. P. & Coimbra, R. Modulating the biologic activity of mesenteric lymph after traumatic shock decreases systemic inflammation and end organ injury. PLoS One 11, e0168322 (2016).

  97. 97.

    Branchfield, K. et al. Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. Science 351, 707–710 (2016).

  98. 98.

    van Wessem, K. J., Hennus, M. P., van Wagenberg, L., Koenderman, L. & Leenen, L. P. Mechanical ventilation increases the inflammatory response induced by lung contusion. J. Surg. Res. 183, 377–384 (2013).

  99. 99.

    Bhandari, V. et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat. Med. 12, 1286–1293 (2006).

  100. 100.

    Greinacher, A. et al. Characterization of the human neutrophil alloantigen-3a. Nat. Med. 16, 45–48 (2010).

  101. 101.

    Kalbitz, M. et al. Cardiac Depression in pigs after multiple trauma — characterization of posttraumatic structural and functional alterations. Sci. Rep. 7, 17861 (2017).

  102. 102.

    Wilson, N. M., Wall, J., Naganathar, V., Brohi, K. & De’Ath, H. D. Mechanisms involved in secondary cardiac dysfunction in animal models of trauma and hemorrhagic shock. Shock 48, 401–410 (2017).

  103. 103.

    McKee, C. A. & Lukens, J. R. Emerging roles for the immune system in traumatic brain injury. Front. Immunol. 7, 556 (2016).

  104. 104.

    Roth, T. L. et al. Transcranial amelioration of inflammation and cell death after brain injury. Nature 505, 223–228 (2014).

  105. 105.

    Braun, M. et al. White matter damage after traumatic brain injury: A role for damage associated molecular patterns. Biochim. Biophys. Acta 1863 10 Pt B, 2614–2626 (2017).

  106. 106.

    Russo, M. V. & McGavern, D. B. Inflammatory neuroprotection following traumatic brain injury. Science 353, 783–785 (2016).

  107. 107.

    Lan, X., Han, X., Li, Q., Yang, Q. W. & Wang, J. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat. Rev. Neurol. 13, 420–433 (2017).

  108. 108.

    Nizamutdinov, D. & Shapiro, L. A. Overview of traumatic brain injury: an immunological context. Brain Sci. http://dx.doi.org/10.3390/brainsci7010011 (2017).

  109. 109.

    Ruseva, M. M., Ramaglia, V., Morgan, B. P. & Harris, C. L. An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proc. Natl. Acad. Sci. USA 112, 14319–14324 (2015).

  110. 110.

    Freeman, L. et al. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J. Exp. Med. 214, 1351–1370 (2017).

  111. 111.

    Bird, L. Neuroimmunology: immune signals packaged in the brain. Nat. Rev. Immunol. 17, 278–279 (2017).

  112. 112.

    Makinde, H. M., Cuda, C. M., Just, T. B., Perlman, H. R. & Schwulst, S. J. Nonclassical monocytes mediate secondary injury, neurocognitive outcome, and neutrophil infiltration after traumatic brain injury. J. Immunol. 199, 3583–3591 (2017).

  113. 113.

    Morganti, J. M. et al. CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury. J. Neurosci. 35, 748–760 (2015).

  114. 114.

    Laird, M. D. et al. High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia 62, 26–38 (2014).

  115. 115.

    Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

  116. 116.

    Sullan, M. J., Asken, B. M., Jaffee, M. S., DeKosky, S. T. & Bauer, R. M. Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy. Neurosci. Biobehav. Rev. 84, 316–324 (2018).

  117. 117.

    Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).

  118. 118.

    Utagawa, A., Truettner, J. S., Dietrich, W. D. & Bramlett, H. M. Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats. Exp. Neurol. 211, 283–291 (2008).

  119. 119.

    Dash, P. K. et al. Activation of α7 cholinergic nicotinic receptors reduce blood-brain barrier permeability following experimental traumatic brain injury. J. Neurosci. 36, 2809–2818 (2016).

  120. 120.

    Diamond, B. & Tracey, K. J. Mapping the immunological homunculus. Proc. Natl. Acad. Sci. USA 108, 3461–3462 (2011).

  121. 121.

    Pavlov, V. A. & Tracey, K. J. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat. Neurosci. 20, 156–166 (2017).

  122. 122.

    Woiciechowsky, C. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat. Med. 4, 808–813 (1998).

  123. 123.

    Di Battista, A. P. et al. Inflammatory cytokine and chemokine profiles are associated with patient outcome and the hyperadrenergic state following acute brain injury. J. Neuroinflammation 13, 40 (2016).

  124. 124.

    Shein, S. L. et al. Hemorrhagic shock shifts the serum cytokine profile from pro- to anti-inflammatory after experimental traumatic brain injury in mice. J. Neurotrauma 31, 1386–1395 (2014).

  125. 125.

    Di Battista, A. P. et al. Sympathoadrenal activation is associated with acute traumatic coagulopathy and endotheliopathy in isolated brain injury. Shock 46, 96–103 (2016).

  126. 126.

    Tian, Y. et al. Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury. Blood 125, 2151–2159 (2015).

  127. 127.

    Maegele, M. et al. Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. Lancet Neurol. 16, 630–647 (2017).

  128. 128.

    Kumar, A. et al. Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury. J. Neuroinflammation 14, 47 (2017).

  129. 129.

    Chang, R., Cardenas, J. C., Wade, C. E. & Holcomb, J. B. Advances in the understanding of trauma-induced coagulopathy. Blood 128, 1043–1049 (2016).

  130. 130.

    Hijazi, N. et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood 125, 2558–2567 (2015).

  131. 131.

    Leinhase, I. et al. Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice. J. Neuroinflammation 4, 13 (2007).

  132. 132.

    Yasui, H., Donahue, D. L., Walsh, M., Castellino, F. J. & Ploplis, V. A. Early coagulation events induce acute lung injury in a rat model of blunt traumatic brain injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 311, L74–L86 (2016).

  133. 133.

    Dai, S. S. et al. Plasma glutamate-modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury-induced acute lung injury. J. Exp. Med. 210, 839–851 (2013).

  134. 134.

    Hu, P. J., Pittet, J. F., Kerby, J. D., Bosarge, P. L. & Wagener, B. M. Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection. Am. J. Physiol. Lung Cell. Mol. Physiol. 313, L1–L15 (2017).

  135. 135.

    Okusa, M. D., Rosin, D. L. & Tracey, K. J. Targeting neural reflex circuits in immunity to treat kidney disease. Nat. Rev. Nephrol. 13, 669–680 (2017).

  136. 136.

    Moore, E. M. et al. The incidence of acute kidney injury in patients with traumatic brain injury. Ren. Fail. 32, 1060–1065 (2010).

  137. 137.

    Lu, R., Kiernan, M. C., Murray, A., Rosner, M. H. & Ronco, C. Kidney-brain crosstalk in the acute and chronic setting. Nat. Rev. Nephrol. 11, 707–719 (2015).

  138. 138.

    Gao, M. et al. Systemic Administration of induced neural stem cells regulates complement activation in mouse closed head injury models. Sci. Rep. 7, 45989 (2017).

  139. 139.

    Nongnuch, A., Panorchan, K. & Davenport, A. Brain-kidney crosstalk. Crit. Care 18, 225 (2014).

  140. 140.

    Molitoris, B. A. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J. Clin. Invest. 124, 2355–2363 (2014).

  141. 141.

    Abe, C. et al. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat. Neurosci. 20, 700–707 (2017).

  142. 142.

    Campbell, S. J. et al. Central nervous system injury triggers hepatic CC and CXC chemokine expression that is associated with leukocyte mobilization and recruitment to both the central nervous system and the liver. Am. J. Pathol. 166, 1487–1497 (2005).

  143. 143.

    Nizamutdinov, D. et al. Hepatic alterations are accompanied by changes to bile acid transporter-expressing neurons in the hypothalamus after traumatic brain injury. Sci. Rep. 7, 40112 (2017).

  144. 144.

    Campbell, S. J. et al. Liver Kupffer cells control the magnitude of the inflammatory response in the injured brain and spinal cord. Neuropharmacology 55, 780–787 (2008).

  145. 145.

    Ma, J. et al. Impacts of blast-induced traumatic brain injury on expressions of hepatic cytochrome P450 1A2, 2B1, 2D1, and 3A2 in rats. Cell. Mol. Neurobiol. 37, 111–120 (2017).

  146. 146.

    Sundman, M. H., Chen, N. K., Subbian, V. & Chou, Y. H. The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. Brain Behav. Immun. 66, 31–44 (2017).

  147. 147.

    Katzenberger, R. J., Ganetzky, B. & Wassarman, D. A. The gut reaction to traumatic brain injury. Fly (Austin) 9, 68–74 (2015).

  148. 148.

    Kozlov, A. V., Bahrami, S., Redl, H. & Szabo, C. Alterations in nitric oxide homeostasis during traumatic brain injury. Biochim. Biophys. Acta 1863, 2627–2632 (2017).

  149. 149.

    Rizoli, S. B. et al. Catecholamines as outcome markers in isolated traumatic brain injury: the COMA-TBI study. Crit. Care 21, 37 (2017).

  150. 150.

    Meisel, C., Schwab, J. M., Prass, K., Meisel, A. & Dirnagl, U. Central nervous system injury-induced immune deficiency syndrome. Nat. Rev. Neurosci. 6, 775–786 (2005).

  151. 151.

    Hazeldine, J., Lord, J. M. & Belli, A. Traumatic brain injury and peripheral immune suppression: primer and prospectus. Front. Neurol. 6, 235 (2015).

  152. 152.

    Gadani, S. P., Smirnov, I., Smith, A. T., Overall, C. C. & Kipnis, J. Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury. J. Exp. Med. 214, 285–296 (2017).

  153. 153.

    Walker, P. A. et al. Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes. Exp. Neurol. 225, 341–352 (2010).

  154. 154.

    Schwulst, S. J., Trahanas, D. M., Saber, R. & Perlman, H. Traumatic brain injury-induced alterations in peripheral immunity. J. Trauma Acute Care Surg. 75, 780–788 (2013).

  155. 155.

    Johansson, M. E. & Hansson, G. C. Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 16, 639–649 (2016).

  156. 156.

    Perez-Lopez, A., Behnsen, J., Nuccio, S. P. & Raffatellu, M. Mucosal immunity to pathogenic intestinal bacteria. Nat. Rev. Immunol. 16, 135–148 (2016).

  157. 157.

    Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 10, 131–144 (2010).

  158. 158.

    Patel, J. J., Rosenthal, M. D., Miller, K. R. & Martindale, R. G. The gut in trauma. Curr. Opin. Crit. Care 22, 339–346 (2016).

  159. 159.

    Sodhi, C. P. et al. Intestinal epithelial TLR-4 Activation is required for the development of acute lung injury after trauma/hemorrhagic shock via the release of HMGB1 from the Gut. J. Immunol. 194, 4931–4939 (2015).

  160. 160.

    Dalle Lucca, J. J. et al. Effects of C1 inhibitor on tissue damage in a porcine model of controlled hemorrhage. Shock 38, 82–91 (2012).

  161. 161.

    Fishman, J. E. et al. Intraluminal nonbacterial intestinal components control gut and lung injury after trauma hemorrhagic shock. Ann. Surg. 260, 1112–1120 (2014).

  162. 162.

    DeLano, F. A., Hoyt, D. B. & Schmid-Schönbein, G. W. Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci. Transl. Med. 5, 169ra11 (2013).

  163. 163.

    Grootjans, J. et al. Level of activation of the unfolded protein response correlates with Paneth cell apoptosis in human small intestine exposed to ischemia/reperfusion. Gastroenterology 140, 529–539 (2011).

  164. 164.

    Moore, F. A. et al. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J. Trauma 31, 629–636 (1991).

  165. 165.

    Buttenschoen, K. et al. Plasma concentrations of endotoxin and antiendotoxin antibodies in patients with multiple injuries: a prospective clinical study. Eur. J. Surg. 162, 853–860 (1996).

  166. 166.

    Charbonney, E. et al. Endotoxemia following multiple trauma: risk factors and prognostic implications. Crit. Care Med. 44, 335–341 (2016).

  167. 167.

    Levy, G. et al. Parasympathetic stimulation via the vagus nerve prevents systemic organ dysfunction by abrogating gut injury and lymph toxicity in trauma and hemorrhagic shock. Shock 39, 39–44 (2013).

  168. 168.

    Deitch, E. A. Gut-origin sepsis: evolution of a concept. Surgeon 10, 350–356 (2012).

  169. 169.

    Lee, M. A., Yatani, A., Sambol, J. T. & Deitch, E. A. Role of gut-lymph factors in the induction of burn-induced and trauma-shock-induced acute heart failure. Int. J. Clin. Exp. Med. 1, 171–180 (2008).

  170. 170.

    Fang, J. F. et al. Proteomic analysis of post-hemorrhagic shock mesenteric lymph. Shock 34, 291–298 (2010).

  171. 171.

    Dai, H., Sun, T., Liu, Z., Zhang, J. & Zhou, M. The imbalance between regulatory and IL-17-secreting CD4+ T cells in multiple-trauma rat. Injury 44, 1521–1527 (2013).

  172. 172.

    Morishita, K., Coimbra, R., Langness, S., Eliceiri, B. P. & Costantini, T. W. Neuroenteric axis modulates the balance of regulatory T cells and T-helper 17 cells in the mesenteric lymph node following trauma/hemorrhagic shock. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G202–G208 (2015).

  173. 173.

    Matteoli, G. & Boeckxstaens, G. E. The vagal innervation of the gut and immune homeostasis. Gut 62, 1214–1222 (2013).

  174. 174.

    Kojima, M. et al. Exosomes, not protein or lipids, in mesenteric lymph activate inflammation: unlocking the mystery of post-shock multiple organ failure. J. Trauma Acute Care Surg. 82, 42–50 (2017).

  175. 175.

    Tiesi, G. et al. Early trauma-hemorrhage-induced splenic and thymic apoptosis is gut-mediated and toll-like receptor 4-dependent. Shock 39, 507–513 (2013).

  176. 176.

    Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).

  177. 177.

    Langness, S., Kojima, M., Coimbra, R., Eliceiri, B. P. & Costantini, T. W. Enteric glia cells are critical to limiting the intestinal inflammatory response after injury. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G274–G282 (2017).

  178. 178.

    Ma, E. L. et al. Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice. Brain Behav. Immun. 66, 56–69 (2017).

  179. 179.

    Oyeniyi, B. T. et al. Trends in 1029 trauma deaths at a level 1 trauma center: Impact of a bleeding control bundle of care. Injury 48, 5–12 (2017).

  180. 180.

    Lefering, R. et al. Epidemiology of in-hospital trauma deaths. Eur. J. Trauma Emerg. Surg. 38, 3–9 (2012).

  181. 181.

    Prin, M. & Li, G. Complications and in-hospital mortality in trauma patients treated in intensive care units in the United States, 2013. Inj. Epidemiol 3, 18 (2016).

  182. 182.

    Spruijt, N. E., Visser, T. & Leenen, L. P. A systematic review of randomized controlled trials exploring the effect of immunomodulative interventions on infection, organ failure, and mortality in trauma patients. Crit. Care 14, R150 (2010).

  183. 183.

    Mann, A. P. et al. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries. Nat. Commun. 7, 11980 (2016).

  184. 184.

    Yang, R. et al. Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol. Med. 12, 105–114 (2006).

  185. 185.

    Ruan, X. et al. Anti-HMGB1 monoclonal antibody ameliorates immunosuppression after peripheral tissue trauma: attenuated T-lymphocyte response and increased splenic CD11b+Gr-1+ myeloid-derived suppressor cells require HMGB1. Mediators Inflamm. 2015, 458626 (2015).

  186. 186.

    Okuma, Y. et al. Anti-high mobility group box-1 antibody therapy for traumatic brain injury. Ann. Neurol. 72, 373–384 (2012).

  187. 187.

    Kimbler, D. E., Shields, J., Yanasak, N., Vender, J. R. & Dhandapani, K. M. Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice. PLoS One 7, e41229 (2012).

  188. 188.

    Abrams, S. T. et al. Circulating histones are mediators of trauma-associated lung injury. Am. J. Respir. Crit. Care Med. 187, 160–169 (2013).

  189. 189.

    Heeres, M. et al. The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial. Trials 12, 223 (2011).

  190. 190.

    Rich, M. C. et al. Site-targeted complement inhibition by a complement receptor 2-conjugated inhibitor (mTT30) ameliorates post-injury neuropathology in mouse brains. Neurosci. Lett. 617, 188–194 (2016).

  191. 191.

    Fluiter, K., Opperhuizen, A. L., Morgan, B. P., Baas, F. & Ramaglia, V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J. Immunol. 192, 2339–2348 (2014).

  192. 192.

    Lee, S. et al. A novel antagonist of p75NTR reduces peripheral expansion and CNS trafficking of pro-inflammatory monocytes and spares function after traumatic brain injury. J. Neuroinflammation 13, 88 (2016).

  193. 193.

    Xu, X. et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J. Neuroinflammation 14, 167 (2017).

  194. 194.

    Yamada, N. et al. Novel synthetic, host-defense peptide protects against organ injury/dysfunction in a rat model of severe hemorrhagic shock. Ann. Surg. http://doi.org/10.1097/SLA.0000000000002186 (2017).

  195. 195.

    Nikolian, V. C. et al. Valproic acid decreases brain lesion size and improves neurologic recovery in swine subjected to traumatic brain injury, hemorrhagic shock, and polytrauma. J. Trauma Acute Care Surg. 83, 1066–1073 (2017).

  196. 196.

    Sordi, R. et al. Artesunate protects against the organ injury and dysfunction induced by severe hemorrhage and resuscitation. Ann. Surg. 265, 408–417 (2017).

  197. 197.

    Laplante, P. et al. MFG-E8 reprogramming of macrophages promotes wound healing by increased bFGF production and fibroblast functions. J. Invest. Dermatol. 137, 2005–2013 (2017).

  198. 198.

    Nielson, J. L. et al. Topological data analysis for discovery in preclinical spinal cord injury and traumatic brain injury. Nat. Commun. 6, 8581 (2015).

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Acknowledgements

We thank R. Halbgebauer and D. McClellan for editorial assistance, and S. Denk for graphical support. Supported by the German Research Foundation (DFG CRC1149 and DFG EI866/5-1), the US National Institutes of Health (AI068730, AI030040) and the European Community’s Seventh Framework Programme (under grant agreement number 602699 (DIREKT)).

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Affiliations

  1. Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany

    • Markus Huber-Lang
  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    • John D. Lambris
  3. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    • Peter A. Ward

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Contributions

All authors researched the data for the article, contributed to discussions of the content, wrote the text and reviewed or edited the article before submission.

Competing interests

M.H.-L. and P.A.W. hold a patent on compositions and methods for the diagnosis and treatment of sepsis (US 7455837). J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogs such as AMY-101), and is the inventor of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2).

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Correspondence to Markus Huber-Lang.

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https://doi.org/10.1038/s41590-018-0064-8