Abstract
In the human body, billions of cells die by apoptosis every day. The subsequent clearance of apoptotic cells by phagocytosis is normally efficient enough to prevent secondary necrosis and the consequent release of cell contents that would induce inflammation and trigger autoimmunity. In addition, apoptotic cells generally induce an anti-inflammatory response, thus removal of apoptotic cells is usually immunologically silent. Since the first discovery that uptake of apoptotic cells leads to transforming growth factor (TGF)-β and interleukin (IL)-10 release by engulfing macrophages, numerous anti-inflammatory mechanisms triggered by apoptotic cells have been discovered, including release of anti-inflammatory molecules from the apoptotic cells, triggering immediate anti-inflammatory signaling pathways by apoptotic cell surface molecules via phagocyte receptors, activating phagocyte nuclear receptors following uptake and inducing the production of anti-inflammatory soluble mediators by phagocytes that may act via paracrine or autocrine mechanisms to amplify and preserve the anti-inflammatory state. Here, we summarize our present knowledge about how these anti-inflammatory mechanisms operate during the clearance of apoptotic cells.
Highlights
Timed initiation of apoptotic type of cell death followed by prompt removal carried out by professional engulfers or by non-professional neighboring cells plays a central role in the maintenance of tissue homeostasis
Adenosine triggers macrophage adenosine A2A receptors (A2ARs) to suppress the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, via activating the adenylate cyclase/protein kinase A pathway [86]. Both adenosine A2A and A3 (A3R) receptors are expressed by macrophages, and while A2ARs inhibit, A3Rs promote the release of neutrophil migration factors by engulfing macrophages [87]
The silent removal of apoptotic cells maintains tissue integrity under healthy conditions and its anti-inflammatory nature contributes to the resolution of inflammation (Figure 1)
Summary
The subsequent clearance of apoptotic cells by phagocytosis is normally efficient enough to prevent secondary necrosis and the consequent release of cell contents that would induce inflammation and trigger autoimmunity. Apoptotic cells generally induce an anti-inflammatory response, removal of apoptotic cells is usually immunologically silent. Since the first discovery that uptake of apoptotic cells leads to transforming growth factor (TGF)-β and interleukin (IL)-10 release by engulfing macrophages, numerous anti-inflammatory mechanisms triggered by apoptotic cells have been discovered, including release of antiinflammatory molecules from the apoptotic cells, triggering immediate anti-inflammatory signaling pathways by apoptotic cell surface molecules via phagocyte receptors, activating phagocyte nuclear receptors following uptake and inducing the production of anti-inflammatory soluble mediators by phagocytes that may act via paracrine or autocrine mechanisms to amplify and preserve the anti-inflammatory state. We summarize our present knowledge about how these anti-inflammatory mechanisms operate during the clearance of apoptotic cells
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