Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer

Abstract

Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.

Programmed Cell Death and Inflammation: Winter Is Coming

“…Indeed, activated T cells expose PS on their surface, yet avoid uptake by phagocytes, possibly through the co-expression of “don't eat me” signals, such as CD47 [70, 71]. Similarly, constitutive PS exposure by mutant TMEM16F can result in rapid and reversible PS externalization, which does not result in phagocytic uptake, contrary to Xkr8-mediated irreversible PS externalization [72]. Recent work has demonstrated that PS exposure and even plasma membrane permeability are not irreversible events during programmed necrosis [23].…”

Protein S and Gas6 induce efferocytosis of HIV-1-infected cells

“…Phagocytosis of dying or dead cells by phagocytes such as macrophages is known as efferocytosis (Birge et al, 2016; Zent and Elliott, 2017). Removal of dead or dying cells by efferocytosis is critical for maintaining homeostasis and preventing inflammation and autoimmune reactions (Elliott and Ravichandran, 2016).…”

In Vitro Cell Death Discrimination and Screening Method by Simple and Cost-Effective Viability Analysis

“…Examples include that mitochondrial cytochrome-c release was observed in cells undergoing necrosis [41], caspase inhibition could delay cell death after plasma membrane disruption [42], caspase-3 activation occurs under physiological conditions not related to cell death [43], apoptosis may occur without DNA cleavage while oncosis may involve such changes [44], PS exposure is involved in numerous (patho-)physiological processes (e.g. platelet activation and swelling-induced erythrocyte haemolysis [45-47]), and, canonical apoptotic stimuli may induce initial cell swelling [48, 49]. …”