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Evidence for anti‐inflammatory effects of C5a on the innate IL‐17A/IL‐23 axis
Author(s) -
Bosmann Markus,
Sarma J. Vidya,
Atefi Gelareh,
Zetoune Firas S.,
Ward Peter A.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-199216
Subject(s) - innate immune system , immunology , medicine , interleukin 17 , inflammation , immune system
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, γ δ 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.—Bosmann, M., Sarma, J. V., Atefi, G., Zetoune, F. S., Ward, P. A. Evidence for anti‐inflammatory effects of C5a on the innate IL‐17A/IL‐23 axis. FASEB J. 26, 1640‐1651 (2012). www.fasebj.org