FIG. 6.

A systems view of innate immune and T-cell-mediated acute inflammation. Trauma leads to early release of DAMPs, stimulating either proinflammatory (M1 macrophages, neutrophils, cytokines such as TNF-α) or anti-inflammatory (M2 macrophages, cytokines such as IL-10) pathways via the early production of defined chemokine subsets. This leads to either the resolution of inflammation via chemokines such as IP-10 or exacerbated inflammation via chemokines such as MIG and MCP-1 in concert with secondary release of DAMPs. In the setting of post-trauma infection, proinflammatory agents (e.g., TNF-α) cause further inflammation and tissue damage/dysfunction. When the positive feedback loop of inflammation→damage→inflammation (indicated in red) exceeds certain thresholds (tipping points), T-cell-mediated responses are initiated via activation of dendritic cells, NK, NK-T cells, cytotoxic T lymphocytes (CTL), and innate lymphoid cells (ILC). T-cell-mediated responses include early (min) γδ T cells and later (4–12 h) Th17 cells. This response either resolves via IL-10, with relatively low systemic spillover of mediators and little organ damage, or propagates in a feed-forward manner, with worsening of organ damage and the attendant elevation of IL-6. Thus, chemokines such as IP-10, MCP-1, and MIG, as well as cytokines such as IL-6 and IL-10 (indicated in blue), can be both biomarkers and potential therapeutic targets under the appropriate circumstances. TNF-α, tumor necrosis factor alpha. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars