Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation

Sho Morioka, Daiki Kajioka, Yusuke Yamaoka, Rochelle M. Ellison, Turan Tufan, Inge L. Werkman, Shinji Tanaka, Brady Barron, Satoshi T. Ito, Sarah Kucenas, Mark D. Okusa, Kodi S. Ravichandran

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of “efferocytosis.” Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted “chimeric receptor for efferocytosis” (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation.

Original languageEnglish
Pages (from-to)4887-4903.e17
JournalCell
Volume185
Issue number26
DOIs
StatePublished - Dec 22 2022

Keywords

  • acute kidney injury
  • apoptosis
  • BAI1
  • CHEF
  • chimeric receptor
  • efferocytosis
  • ELMO1
  • inflammatory diseases
  • TIM4

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