Figure 1.

Mechanisms of the anti-inflammatory effects of apoptotic cells. Apoptotic cells release various anti-inflammatory molecules, such as transforming growth factor (TGF)-β, interleukin (IL)-10, annexin I, thrombospondin-1 (TSP-1), fractalkine to inhibit pro-inflammatory cytokine formation of phagocytes. Once released from the apoptotic cells via a caspase-regulated pannexin channel, ATP is fast degraded to adenosine by the cell surface 5′ nucleotidase of engulfing macrophages. Adenosine then triggers macrophage adenosine A_2A receptors to suppress the NO-dependent formation of neutrophil migration factors, or in an inflammatory milieu the lipopolysaccharide (LPS)-induced pro-inflammatory cytokine formation by phagocytes. Apoptotic cells express phosphatidylserine (PS), which activates various PS sensing phagocytic receptors. Many of these receptors initiate such intracellular signaling pathways that interfere with the pro-inflammatory cytokine formation of phagocytes. Following engulfment, the lipid content of the apoptotic cells activate the nuclear lipid sensing receptors [liver X receptors (LXRs) and perixosome proliferator-activated receptors (PPARs)], which in ligated form can also interfere with the NF-κB-driven pro-inflammatory cytokine formation. And, finally, engulfing macrophages release TGF-β, IL-10, and retinoids, which act in a paracrine or autocrine fashion to amplify and sustain the anti-inflammatory response and strongly contribute to the formation of the regulatory T cells to prevent the development of autoimmunity.