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The formation of the 'footprint of death' as a mechanism for generating large substrate-bound extracellular vesicles that mark the site of cell death

ABSTRACT: Apoptotic cells communicate to phagocytic cells through releasing soluble factors and apoptotic cell derived extracellular vesicles. However, whether there are additional factors that remain attached at the site of cell death to signal to phagocytic cells is currently unknown. Here we show that apoptotic cell retraction generates a membrane encased, F actin rich ‘footprint’ tightly anchored to the substrate that marks the site of cell death, coined ‘the FOotprint Of Death’ or FOOD. Formation of FOOD is observed frequently across many different cell types, apoptotic stimuli and surface composition. Mechanistically, FOOD formation is regulated by the protein kinase ROCK1. 3D time lapse microscopy studies revealed that FOOD vesicularises into distinct large extracellular vesicles. These extracellular vesicles expose the ‘eat me’ signal phosphatidylserine and can function to ‘flag’ the site of cell death to neighbouring phagocytes for efferocytosis. Under a viral infection setting, FOOD can harbour viral proteins and virions, and propagate infection to healthy cells. Together, this study has revealed another route of apoptotic cell phagocyte communication.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Epithelial Cell Migration

SUBMITTER: Ching-Seng Ang

LAB HEAD: Ivan Poon

PROVIDER: PXD067718 | Pride | 2025-10-15

REPOSITORIES: Pride

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			Action	DRS
	210510_Pam_PM-2242_APO_1-1.raw	Raw
	210510_Pam_PM-2242_APO_1-10.raw	Raw
	210510_Pam_PM-2242_APO_1-2.raw	Raw
	210510_Pam_PM-2242_APO_1-3.raw	Raw
	210510_Pam_PM-2242_APO_1-4.raw	Raw

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Project description:Natural antibodies, which arise without known immune exposure, have been described that specifically recognize cells dying from apoptosis but their role in innate immunity remains poorly understood. Herein, we show that the immune response to neo-antigenic determinants on apoptotic thymocytes is dominated by antibodies to oxidation-associated antigens, phosphorylcholine (PC), a head group that becomes exposed during programmed-cell death, and malondialdehyde (MDA), a reactive aldehyde degradation product of polyunsaturated lipids produced following exposure to reactive-oxidation species. While natural antibodies to apoptotic cells in naM-CM-/ve adult mice were dominated by PC and MDA specificities, the amounts of these antibodies were substantially boosted by treatment of mice with apoptotic cells. Moreover, the relative amounts of PC and MDA antibodies was affected by VH gene inheritance. Antibody interactions with apoptotic-cells also mediated the recruitment of C1q, which alone can promote apoptotic-cell phagocytosis by immature dendritic cells. Significantly, IgM-antibodies to both PC and MDA were primary factors in determining the efficiency of serum-dependent apoptotic-cell phagocytosis. Hence, we demonstrate a mechanism by which certain natural antibodies that recognize neo-antigens on apoptotic cells, in naM-CM-/ve mice and those induced by immune exposure to apoptotic-cells, can enhance the functional capabilities of immature dendritic cells for phagocytic engulfment of apoptotic cells. Keywords: Natural antibodies, Inflammation, Complement, Apoptosis In the study presented here, a total of 11 custom-spotted protein slides were hybridized with a T15 IgM monoclonal antibody at three different concentrations, an isotype control IgM, 2 slides were hybridized with serum from naM-QM-^Wve mice, 2 slides incubated with serum from mice immunized with apoptotic cells, 2 slides were incubated with serum from mice immunized with saline, and a negative control slide with no antibody hybridized

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The formation of the 'footprint of death' as a mechanism for generating large substrate-bound extracellular vesicles that mark the site of cell death

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