Title

Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis.

Document Type

Journal Article

Publication Date

4-1-2012

Journal

The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Volume

26

Issue

4

DOI

10.1096/fj.11-199216

Keywords

Animals; Anti-Inflammatory Agents; Antigens, Differentiation; CD11b Antigen; Complement C5a; Extracellular Signal-Regulated MAP Kinases; Immunity, Innate; Interleukin-10; Interleukin-17; Interleukin-23; Interleukin-23 Subunit p19; Lipopolysaccharides; MAP Kinase Kinase 1; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Toll-Like Receptor 4

Abstract

There is growing evidence that the complement activation product C5a positively or negatively regulates inflammatory functions. The studies presented here report that C5a exerts anti-inflammatory effects by altering production of the cytokines IL-17A and IL-23 during endotoxic shock in young adult male C57BL/6J mice and has similar effects on macrophages from the same mice. IL-17A and IL-23 both appeared in plasma during endotoxemia, and their neutralization improved survival. The relevant sources of IL-17A during endotoxemia were not CD4(+) cells, γδ T cells, or NK cells but CD11b(+)F4/80(+) macrophages. The addition in vitro of C5a to lipopolysaccharide-activated peritoneal macrophages dose dependently antagonized the production of IL-17A (IC(50), 50-100 nM C5a) and IL-23 (IC(50), 10 nM C5a). This suppression required the receptor C5aR, but was independent of the second C5a receptor, C5L2. Genetic absence of C5aR was associated with much higher levels of IL-17A and IL-23 during endotoxic shock. Mechanistically, C5a mediated its effects on the IL-17A/IL-23 axis in a 2-step process. C5a caused activation of the PI3K-Akt and MEK1/2-ERK1/2 pathways, resulting in induction of IL-10, which powerfully inhibited production of IL-17A and IL-23. These data identify previously unknown mechanisms by which the anaphylatoxin C5a limits acute inflammation and antagonizes the IL-17A/IL-23 axis.

Comments

This is an open access PubMed Central article.

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