Abstract
The immunosuppressive effects of apoptotic cells involve inhibition of pro-inflammatory cytokine release and establishment of an anti-inflammatory cytokine profile, thus limiting the degree of inflammation and promoting resolution. We report here that this is in part mediated by the release of the anti-inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor (FPR) family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2-26 significantly reduced IL-6 signalling and the release of TNF-α from endotoxin-challenged monocytes. Ac2-26 activated STAT3 in a JAK-dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2-26-mediated inhibition of IL-6 signalling. This identifies annexin A1 as part of the anti-inflammatory pattern of apoptotic cells and links the activation of FPRs to established signalling pathways triggering anti-inflammatory responses.
Highlights
Apoptotic cells play an important regulatory role in inflammation and immune responses
Anti-inflammatory mediators released from apoptotic cells activate the JAK/STAT pathway We first examined the effects of mediators released by apoptotic human neutrophils on the lipopolysaccharide (LPS, Calbiochem)-induced TNF-a release in monocytes
Human monocytes were pre-treated with culture supernatants obtained from apoptotic neutrophils, challenged with LPS and the levels of released TNF-a were determined by enzyme-linked immunosorbent assay (ELISA; Immunotools)
Summary
Apoptotic cells play an important regulatory role in inflammation and immune responses. Clearance of dying cells by phagocytosis protects the tissue at inflammatory sites from exposure to contents released from disintegrated cells. The regulatory effect of apoptotic cells goes beyond the safe disposal of unwanted dangerous material. The phagocytic clearance of apoptotic neutrophils, for example, is antiinflammatory and contributes to the resolution of inflammation by actively regulating the immune response (Fadok et al, 1998; Savill & Fadok, 2000; Voll et al, 1997). The pathogenesis of autoimmune diseases has been linked to inefficient clearance of apoptotic cells (Gregory & Devitt, 2004)
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