Everyday, billions of cells within the human body will die as a result of programmed cell death through apoptosis. Although the induction of apoptosis and removal of apoptotic cells has been thoroughly studied, the intermediate step where the cell can disassemble into small apoptotic bodies (ApoBDs, through a process called apoptotic cell disassembly) has remained elusive. However, we recently identified a new mechanism of monocyte ApoBD formation through discovery of a beaded-necklace like membrane protrusion (beaded-apoptopodia). Excitingly, these findings indicated that the disassembly of apoptotic monocytes may be a controlled process with important functional significance.
Biochemical analysis led to the discovery of the membrane channel Pannexin 1 and membrane receptor Plexin B2, as the first negative and positive regulator of monocyte beaded-apoptopodia and ApoBD formation, respectively. Strikingly, the impaired ability to generate beaded-apoptopodia significantly compromised the uptake of apoptotic monocytes by surrounding phagocytes, identifying a fundamental role of cell disassembly in efficient apoptotic cell clearance.
To further assess the functional consequence of monocyte ApoBD formation we used influenza A virus (IAV) as a proof-of-concept model. We confirmed the induction of monocyte apoptotic cell disassembly in vitro and in vivo and found that monocyte ApoBDs could harbour IAV biomolecules and lethal virions. Consequentially, monocyte ApoBDs could propagate IAV infection and induce a robust anti-viral innate and adaptive immune response. However, through the identification of a novel inhibitor of apoptotic cell disassembly, we identified the first compound that can target ApoBD formation in vivo and consequentially, reduce ApoBD-mediated disease severity during IAV infection.
Together, these results have significantly aided our understanding of apoptosis by elucidating the tight molecular control underpinning ApoBD formation and their functional significance. Although important for efficient cell clearance, the generation of ApoBDs may also aid the spread of infectious disease and thus, represent a novel double-edged sword of cell biology.