GPR34-mediated sensing of lysophosphatidylserine released by apoptotic neutrophils activates type 3 innate lymphoid cells to mediate tissue repair

Xiaqiong Wang; Juan Cai; Bolong Lin; Ming Ma; Ye Tao; Yubo Zhou; Li Bai; Wei Jiang; Rongbin Zhou

doi:10.1016/j.immuni.2021.05.007

GPR34-mediated sensing of lysophosphatidylserine released by apoptotic neutrophils activates type 3 innate lymphoid cells to mediate tissue repair

Immunity. 2021 Jun 8;54(6):1123-1136.e8. doi: 10.1016/j.immuni.2021.05.007.

Authors

Xiaqiong Wang¹, Juan Cai², Bolong Lin², Ming Ma², Ye Tao², Yubo Zhou², Li Bai², Wei Jiang³, Rongbin Zhou⁴

Affiliations

¹ Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China; Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
² Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
³ Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: ustcjw@ustc.edu.cn.
⁴ Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China; Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei 230027, China. Electronic address: zrb1980@ustc.edu.cn.

PMID: 34107271
DOI: 10.1016/j.immuni.2021.05.007

Abstract

Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34^-/- mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.

Keywords: DAMP-sensing receptor; GPR34; IL-22; Type 3 innate lymphoid cells; neutrophils; tissue damage; tissue repair.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / immunology*
Cells, Cultured
Colitis / immunology
Colon / immunology
Homeostasis / immunology
Humans
Immunity, Innate / immunology*
Interleukin-22
Interleukins / immunology
Intestinal Mucosa / immunology
Lymphocytes / immunology*
Lysophospholipids / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils / immunology*
Phosphatidylinositol 3-Kinases / immunology
Receptors, Lysophospholipid / immunology*

Substances

G-protein-coupled receptor 34
Interleukins
Lysophospholipids
Receptors, Lysophospholipid
lysophosphatidylserine