FAS-induced cytokine production promotes phagocyte chemotaxis toward apoptotic cells.
Major finding: FAS-induced cytokine production promotes phagocyte chemotaxis toward apoptotic cells.
Mechanism: IAP activity and RIPK1-induced NF-κB activation are required for optimal cytokine production.
Impact: Some types of apoptosis are immunogenic and engage the immune system for dying cell clearance.
Apoptosis is generally considered an immunologically silent form of cell death that does not actively engage the immune system or elicit an inflammatory response. Recent studies have indicated that apoptotic cells can in fact secrete soluble factors such as ATP that attract phagocytic cells and promote clearance of dying cells, but whether apoptotic cells can send conventional chemotactic signals through secretion of cytokines remains unclear. Because stimulation of the FAS receptor, which induces caspase-8–dependent apoptosis, has also been linked with production of proinflammatory cytokines in nonapoptotic immune cells, Cullen and colleagues tested whether FAS-dependent apoptosis is associated with cytokine secretion. FAS receptor stimulation concurrently triggered high levels of apoptosis and cytokine secretion in multiple nonimmune human cell types, suggesting that cytokine release is a general feature of FAS receptor activation. Mechanistically, inhibitor of apoptosis (IAP) proteins, known regulators of FAS-dependent apoptosis, were required for FAS-induced cytokine production, as was activation of NF-κB signaling by the downstream effector RIP kinase 1 (RIPK1). The supernatants of FAS-stimulated apoptotic cells were strongly chemotactic for human monocytes and neutrophils, and macrophages rapidly accumulated at sites of FAS-induced cell death in vivo, providing evidence that a consequence of FAS-induced cytokine release is phagocytic cell recruitment. Systematic evaluation of the effect of depleting components of FAS-stimulated supernatants on chemotactic activity revealed that monocyte chemotactic protein-1 and interleukin-8, but not ATP, were required for migration of phagocytes toward the supernatants from FAS-stimulated apoptotic cells. These results provide further support for the idea that certain types of apoptotic cell death are immunogenic and indicate that some proapoptotic stimuli can promote the release of chemotactic cytokines to facilitate the phagocytic removal of dying cells.