Chemokines act as phosphatidylserine-bound "find-me" signals in apoptotic cell clearance

PLoS Biol. 2021 May 26;19(5):e3001259. doi: 10.1371/journal.pbio.3001259. eCollection 2021 May.

Abstract

Removal of apoptotic cells is essential for maintenance of tissue homeostasis. Chemotactic cues termed "find-me" signals attract phagocytes toward apoptotic cells, which selectively expose the anionic phospholipid phosphatidylserine (PS) and other "eat-me" signals to distinguish healthy from apoptotic cells for phagocytosis. Blebs released by apoptotic cells can deliver find-me signals; however, the mechanism is poorly understood. Here, we demonstrate that apoptotic blebs generated in vivo from mouse thymus attract phagocytes using endogenous chemokines bound to the bleb surface. We show that chemokine binding to apoptotic cells is mediated by PS and that high affinity binding of PS and other anionic phospholipids is a general property of many but not all chemokines. Chemokines are positively charged proteins that also bind to anionic glycosaminoglycans (GAGs) on cell surfaces for presentation to leukocyte G protein-coupled receptors (GPCRs). We found that apoptotic cells down-regulate GAGs as they up-regulate PS on the cell surface and that PS-bound chemokines, unlike GAG-bound chemokines, are able to directly activate chemokine receptors. Thus, we conclude that PS-bound chemokines may serve as find-me signals on apoptotic vesicles acting at cognate chemokine receptors on leukocytes.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis* / immunology
  • Apoptosis* / physiology
  • CHO Cells
  • Cell Membrane / metabolism
  • Chemokines* / metabolism
  • Chemokines* / physiology
  • Chemotaxis
  • Cricetulus
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phagocytes / metabolism
  • Phagocytosis / physiology
  • Phosphatidylserines / metabolism
  • Receptors, Chemokine / metabolism
  • Signal Transduction / physiology

Substances

  • Chemokines
  • Phosphatidylserines
  • Receptors, Chemokine

Grants and funding

The National Institute of Allergy and Infectious Diseases-Intramural Research Program (grant number N/A) supported SMP, PMM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.