Evidence for anti‐inflammatory effects of C5a on the innate IL‐17A/IL‐23 axis
Open accessAbstract
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
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In animal models, reducing neutrophil invasion through IL-17A-blocking antibody has been shown to decrease infarct size and improve neurologic outcome in ischemic stroke, and has been shown to improve survival in endotoxic shock.
“In animal models, reducing neutrophil invasion through IL-17A-blocking antibody has been shown to decreased infarct size and improved neurologic outcome in ischemic stroke [31] and has been shown to improve survival in endotoxic shock [32,33].”
From Oral neutrophils are an independent marker of the systemic inflammatory response after cardiac bypass (2014) · cites this paper as [32]
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References 51 · Cited by 67
- Authors
- Bosmann, M., Sarma, J. V., Atefi, G., Zetoune, F. S., & Ward, P. A.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Ward, Peter A.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2011-12-27
- Volume
- 26
- Issue
- 4
- Pages
- 1640-1651
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC3316904
- OpenAlex
- W2161365997
- Cited by
- 67
- References
- 51
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 8 · 2018: 2 · 2017: 3 · 2016: 7 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- National Institutes of Health (GM‐29507, GM‐61656)
- Deutsche Forschungsgemeinschaft (571701, BO 3482/1‐1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- C5a, complement activation, IL-17A, IL-23, endotoxic shock, endotoxemia, macrophages, C5a receptor, C5L2, PI3K/Akt signaling, MEK/ERK signaling, IL-10, anaphylatoxins, anti-inflammatory activity, acute inflammation
- MeSH terms
- Animals, Anti-Inflammatory Agents, Antigens, Differentiation, Immunity, Innate, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Signal Transduction, Complement C5a, Interleukin-10, Mice, Knockout, Phosphatidylinositol 3-Kinases, Interleukin-17, CD11b Antigen, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 1, Proto-Oncogene Proteins c-akt, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88, Interleukin-23, Interleukin-23 Subunit p19
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