Funerals and Feasts: The Immunological Rites of Cell Death

Abstract

The immune system functions as a vanguard against pathogens and toxins. While it is mostly considered to be activated on the basis of self versus non-self recognition, injury/infection and damage are unavoidably associated with cell death. Does cell death play a role in the regulation of the immune response? Cell death, for better or for worse, is an omnipresent process in all stages of life that are observed throughout most tissues in multicellular organisms. From development to homeostasis in adult organisms, cells commit to scheduled death, while cases of injury and infection result in unscheduled cell death. Novel understanding of the molecular mechanisms that govern cell death demonstrate that, in fact, a plethora of molecular processes participate in directed dying. Parallel to the molecular modalities directing cell death are machineries employed by the organism to respond to dying cells, including either eliciting an inflammatory or immunological response or altogether avoiding it. Disturbing the careful coupling of these two processes is often met with pathology - on one hand a failure to respond to cell death may contribute to the lack of proper immune response or defective development, and on the other hand exaggerated or aberrant response to cell death can trigger unregulated inflammation, autoimmunity, or fibrosis/scarring. Here we review the molecular mechanisms and associated effector responses that accompany some of the most well-known cell death modalities - with an emphasis on efferocytosis, a process by which the dead cell is recognized and engulfed. In doing so, we highlight the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases (RTKs) that functions dually in the recognition and engulfment of dead cells, and as an important negative regulator of inflammation.

Keywords: AXL; MERTK; TAM RTKs; TYRO3; apoptosis; cell clearance; cell death; efferocytosis; ferroptosis; necroptosis; necrosis; pyroptosis.