Regulation of Mesenchymal Cell Fate by Transfer of Active Gasdermin-D via Monocyte-Derived Extracellular Vesicles

Abstract

Fibrosis is characterized by inappropriately persistent myofibroblast accumulation and excessive extracellular matrix deposition with the disruption of tissue architecture and organ dysfunction. Regulated death of reparative mesenchymal cells is critical for normal wound repair, but profibrotic signaling promotes myofibroblast resistance to apoptotic stimuli. A complex interplay between immune cells and structural cells underlies lung fibrogenesis. However, there is a paucity of knowledge on how these cell populations interact to orchestrate physiologic and pathologic repair of the injured lung. In this context, gasdermin-D (GsdmD) is a cytoplasmic protein that is activated following cleavage by inflammatory caspases and induces regulated cell death by forming pores in cell membranes. This study was undertaken to evaluate the impact of human (Thp-1) monocyte-derived extracellular vesicles and GsdmD on human lung fibroblast death. Our data show that active GsdmD delivered by monocyte-derived extracellular vesicles induces caspase-independent fibroblast and myofibroblast death. This cell death was partly mediated by GsdmD-independent induction of cellular inhibitor of apoptosis 2 (cIAP-2) in the recipient fibroblast population. Our findings, to our knowledge, define a novel paradigm by which inflammatory monocytes may orchestrate the death of mesenchymal cells in physiologic wound healing, illustrating the potential to leverage this mechanism to eliminate mesenchymal cells and facilitate the resolution of fibrotic repair.

Hijacking homeostasis: Regulation of the tumor microenvironment by apoptosis

“…301 Other homeostatic programs affecting cell survival and population dynamics such as autophagy 302 and senescence 303 will undoubtedly also play key contributory roles in oncogenesis and progression of malignant diseases in the complex circuitry of cancer tissues alongside apoptosis and other cell death modalities, including regulated, caspase-independent cell death, which can be mediated in certain contexts by EVs. 304 Understanding the integration of the multitude of cell death and environmental signals that determine specific efferocyte responses is hugely challenging (reviewed in 305 ) and one of the most intriguing questions in the apoptosis field is how (and why) so many receptors and opsonins are deployed in efferocytosis. Among other possibilities, this may relate to redundancy, cell and tissue context, and functional variation.…”

“…In addition, “cooperation” between different subroutines of regulated cell death may occur to promote tumor growth, a recent report suggesting that pro‐inflammatory efferocytosis of apoptotic cells, caspase 1‐induced, gasdermin D‐independent, NLRP3‐dependent inflammasome activation and resultant IL‐1β production has tumor‐promoting properties which may be important in inflammation‐driven tumor progression in head and neck squamous cell carcinomas 301 . Other homeostatic programs affecting cell survival and population dynamics such as autophagy 302 and senescence 303 will undoubtedly also play key contributory roles in oncogenesis and progression of malignant diseases in the complex circuitry of cancer tissues alongside apoptosis and other cell death modalities, including regulated, caspase‐independent cell death, which can be mediated in certain contexts by EVs 304 …”

“… 301 Other homeostatic programs affecting cell survival and population dynamics such as autophagy 302 and senescence 303 will undoubtedly also play key contributory roles in oncogenesis and progression of malignant diseases in the complex circuitry of cancer tissues alongside apoptosis and other cell death modalities, including regulated, caspase‐independent cell death, which can be mediated in certain contexts by EVs. 304 …”