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. Author manuscript; available in PMC: 2009 Dec 2.
Published in final edited form as: Nat Rev Immunol. 2008 Oct;8(10):776–787. doi: 10.1038/nri2402

Figure 1. Central hubs of the inflammatory response in sepsis.

Figure 1

During sepsis, the complement anaphylatoxin C5a is generated following the activation of the complement system and by the C5-convertase activity of thrombin of the coagulation cascade. C5a triggers the release of pro-inflammatory mediators, including macrophage migration-inhibitory factor (MIF) and high-mobility group box 1 protein (HMGB1), and it activates the coagulation cascade by inducing tissue-factor expression (not shown). HMGB1 is a pleiotropic cytokine that binds to Toll-like receptor 4 (TLR4) and acts as an endogenous alarmin to increase the release of pro-inflammatory mediators. TLR4-mediated responses, in turn, are negatively regulated by C5a. Similar to HMGB1, large amounts of MIF are released during sepsis, which promotes a pro-inflammatory response by amplifying cytokine secretion through the upregulation of TLR4 expression. MIF, which is produced by the pituitary gland as well as by leukocytes, inhibits the anti-inflammatory effects of endogenous glucocorticoids of the endocrine system, which, in turn, induce MIF secretion. HMGB1 links the immune response with the autonomic nervous system, which regulates the release of HMGB1 and other cytokines during sepsis. Interleukin-17A (IL-17A), which is an important regulator of inflammation at the interface between innate and adaptive immunity, orchestrates responses of both innate and adaptive immune cells.