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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / immunology*
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Anti-Inflammatory Agents / pharmacology
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Antigens, Differentiation / immunology
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CD11b Antigen / immunology
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Complement C5a / immunology*
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Complement C5a / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Immunity, Innate / immunology*
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Interleukin-10 / immunology
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Interleukin-17 / immunology*
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Interleukin-23 / immunology*
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Interleukin-23 Subunit p19 / immunology
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Lipopolysaccharides / immunology
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase 1 / metabolism
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88 / immunology
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / immunology
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Toll-Like Receptor 4 / immunology
Substances
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Anti-Inflammatory Agents
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Antigens, Differentiation
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CD11b Antigen
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Interleukin-17
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Interleukin-23
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Interleukin-23 Subunit p19
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Lipopolysaccharides
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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monocyte-macrophage differentiation antigen
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Interleukin-10
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Complement C5a
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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Map2k1 protein, mouse