Plasma membrane repair empowers the necrotic survivors as innate immune modulators

Abstract

The plasma membrane is crucial to the survival of animal cells, and damage to it can be lethal, often resulting in necrosis. However, cells possess multiple mechanisms for repairing the membrane, which allows them to maintain their integrity to some extent, and sometimes even survive. Interestingly, cells that survive a near-necrosis experience can recognize sub-lethal membrane damage and use it as a signal to secrete chemokines and cytokines, which activate the immune response. This review will present evidence of necrotic cell survival in both in vitro and in vivo systems, including in C. elegans, mouse models, and humans. We will also summarize the various membrane repair mechanisms cells use to maintain membrane integrity. Finally, we will propose a mathematical model to illustrate how near-death experiences can transform dying cells into innate immune modulators for their microenvironment. By utilizing their membrane repair activity, the biological effects of cell death can extend beyond the mere elimination of the cells.

Keywords: Chemokines; ESCRT; Innate immunity; Membrane damage repair; Plasma membrane damage; Programmed necrosis; Tetraspanin.

Figure 1.. Cells can come back from programmed cell death.

Cell death is not a “one-way” street. Many mechanisms can halt cell death. Apoptosis, necroptosis, and pyroptosis can even be rescued from the edge of death.

Figure 2.. Overview of membrane repair mechanisms.

(A) Outward shedding of the damaged PM can be mediated by the ESCRT complex. Wounding-induced Ca²⁺ influx sensors ALIX and ALG-2 are necessary to assemble the ESCRT complex. (B) Inward endocytosis mediated by ASM, clathrin, and caveolin can internalize and degrade the damaged membrane in multivesicular bodies (MVB). (C) A damaged membrane can undergo self-resealing under two opposite forces: line and membrane tension. Actin ring contraction beneath the wound and Annexin4/5 activation facilitate wound closure. (D) Patching model, a patch is formed by the fusion of intracellular vesicles or lysosomes and fuses with the damaged PM, mediated by SNARE complexes.

Figure 3.. Membrane repair processes in the C. elegans epidermal cell hyp7 after wounding.

The repair process occurs in three stages: early wound response, repair, and remodeling. During the early response phase, signals such as Ca²⁺ and mitochondrial ROS are produced after PM damage. Later, these signals activate various repair pathways in the repair phase, such as promoting actin ring assembly and recruiting repair machineries, including TSP-15, SYX-2, and EFF-1, to the wound site. Finally, in the remodeling phase, a scar-like structure develops in the cuticle, involving collagen deposition and possibly negatively regulated by DAPK-1.

Figure 4.. Side-by-side comparison of the yeast CWI pathway and mammalian PMI pathway.

It shows cellular barrier damage sensing and repair is an evolutionarily conserved mechanism.

Figure 5.. Membrane repair and the PMI pathway influence the effector responses of cell death.

Cells without PM repair mechanisms die rapidly, limiting PMI-mediated immune modulator production, while they can still affect “$ℰnv$” with DAMP release and by efferocytosis. On the other hand, membrane repair allows cells time “$\mathit{t}$”, to make PMI products to alter the environment “$ℰnv$” in addition to DAMP release and efferocytosis. If repair is successful, cells can survive but still modify “$ℰnv$” with PMI-related secretion, bypassing phagocytes’ engulfment.