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Fig. 3 | Intensive Care Medicine Experimental

Fig. 3

From: Sepsis with liver dysfunction and coagulopathy predicts an inflammatory pattern of macrophage activation

Fig. 3

Cell and inflammatory mediator interplay potentially contributes to the development of HBD + DIC in septic patients. Sepsis-induced NK cell deficiency triggers latent viral reactivation, with viral DNA initiating a TLR9-MyD88-mediated signaling cascade [6, 52]. Subsequent inflammasome activation leads to the secretion of IL-18 and IL-1β [6, 56]. In addition to mediating liver injury [59], IL-1β increases transcription and translation of ferritin [60], and production of IL-6 [5]. The release of damage associated molecular patterns (DAMPs), such as mitochondrial DNA or hemoglobin after tissue injury or hemolysis, triggers macrophage activation independent of IFN-γ. Release of free hemoglobin increases hemoglobin-haptoglobin complexes, activating macrophages to produce extracellular ferritin through the CD163 receptor [6, 56]. Ferritin promotes expression of IL-1β and TLR9 [57, 58], resulting in a positive feedback loop with amplification of inflammatory signals [56]. IL-18, in combination with a secondary signal, such as IL-12 or TLR ligands, activates NK cells to produce IFN-γ [53, 64]. We hypothesize, though, that in the context of sepsis with HBD + DIC, NK cells are limited in their responsiveness to IL-18 due to IL-10-mediated downregulation of the IL-18R [55]. As a result, circulating IFN-γ levels are reduced. However, IL-6 enhances signaling through TLRs, increasing the secretion of proinflammatory mediators, including CXCL10 [5]. Persistent NK cell cytolytic dysfunction, stemming from decreased cell number [52] and high levels of IL-6 [54], translates into an impaired ability to induce apoptosis of activated macrophages [6]. In addition, inflammatory mediators produced by macrophages reinforce macrophage (ferritin, IL-6, IL-1β, IL-12, TNF), pDC (ferritin), and lymphocyte (IL-18, IL-12, CXCL10) activation. Thus, the inflammatory cycle continues unabated (cytokine storm), resulting in organ dysfunction and death in the absence of appropriate therapies. The role of pDC- and NK cell-derived IFN-γ in macrophage activation during sepsis remains unclear. In our study, IFN-γ levels were low, although two of its downstream mediators, CXCL10 and IL-18BP, were elevated in patients with sepsis and HBD + DIC

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