Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis.
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.
Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-5602, USA.
Markus
M
Bosmann
J Vidya
JV
Sarma
Gelareh
G
Atefi
Firas S
FS
Zetoune
Peter A
PA
Ward
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology* / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology; D015936:Complement C5a / Q000276:immunology* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
D000893:Anti-Inflammatory Agents; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C036763:monocyte-macrophage differentiation antigen; D016753:Interleukin-10; D015936:Complement C5a; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse