Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms.

Zao Li,Prashant Raghavan,Yuji Nagaoka,Zheng Zhou,Victor Venegas,Anjon Audhya,Yoshinobu Nakanishi,Eri Morino,Danielle A Garsin

doi:10.1371/journal.pgen.1005285

Zao Li, Prashant Raghavan + Show 7 more

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https://doi.org/10.1371/journal.pgen.1005285

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Abstract

Necrosis, a kind of cell death closely associated with pathogenesis and genetic programs, is distinct from apoptosis in both morphology and mechanism. Like apoptotic cells, necrotic cells are swiftly removed from animal bodies to prevent harmful inflammatory and autoimmune responses. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in the excitotoxic necrosis of six touch neurons and their subsequent engulfment and degradation inside engulfing cells. How necrotic cells are recognized by engulfing cells is unclear. Phosphatidylserine (PS) is an important apoptotic-cell surface signal that attracts engulfing cells. Here we observed PS exposure on the surface of necrotic touch neurons. In addition, the phagocytic receptor CED-1 clusters around necrotic cells and promotes their engulfment. The extracellular domain of CED-1 associates with PS in vitro. We further identified a necrotic cell-specific function of CED-7, a member of the ATP-binding cassette (ABC) transporter family, in promoting PS exposure. In addition to CED-7, anoctamin homolog-1 (ANOH-1), the C. elegans homolog of the mammalian Ca2+-dependent phospholipid scramblase TMEM16F, plays an independent role in promoting PS exposure on necrotic cells. The combined activities from CED-7 and ANOH-1 ensure efficient exposure of PS on necrotic cells to attract their phagocytes. In addition, CED-8, the C. elegans homolog of mammalian Xk-related protein 8 also makes a contribution to necrotic cell-removal at the first larval stage. Our work indicates that cells killed by different mechanisms (necrosis or apoptosis) expose a common “eat me” signal to attract their phagocytic receptor(s); furthermore, unlike what was previously believed, necrotic cells actively present PS on their outer surfaces through at least two distinct molecular mechanisms rather than leaking out PS passively.

Highlights

Cell death during animal development and under pathological conditions is important for removing unwanted cells that are often harmful
We found that necrotic neurons actively present PS to their outer surface through two parallel molecular mechanisms, one of which is shared by cells undergoing apoptosis, a “cell suicide” event, whereas the other is unique to necrotic cells
Our findings reveal novel necrotic cell-specific “eat me” signal-exposure mechanisms and indicate that cells that die through different mechanisms utilize both common and unique mechanisms to attract engulfing cells

Summary

Introduction

Cell death during animal development and under pathological conditions is important for removing unwanted cells that are often harmful. Necrosis was historically considered an uncontrolled cell death event caused by acute damage, recent discoveries made in multiple organisms demonstrated that in addition to injury-induced necrosis, cells possess genetic pathways that trigger necrosis in response to extracellular or intracellular stimuli (reviewed in [8,9,10,11]). Efficient clearance of necrotic cells from animal bodies helps to resolve the wounded area; cell-corpse removal is essential for reducing harmful inflammatory and auto-immune responses induced by the contents of necrotic cells [15,17]. It is currently unclear how necrotic cells expose the “eat me” signal molecules on their surfaces to attract engulfing cells

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