RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome

Yang Ye; Qian Yang; Jinling Wei; Chenxi Shen; Haixing Wang; Rong Zhuang; Yuan Cao; Yajun Ding; Haoran Xu; Shuyang Xiang; Hongxia Mei; Zhongwang Li; Xiya Ren; Chen Zhang; Ji Xiao; Shengxing Zheng; Ting Li; Ruifeng Zeng; Huacheng Liu; Han Lin; Wangning Shang-Guan; Ming Li; Shengwei Jin; Qian Wang

doi:10.1016/j.jare.2024.01.017

RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome

J Adv Res. 2024 Jan 17:S2090-1232(24)00030-4. doi: 10.1016/j.jare.2024.01.017. Online ahead of print.

Authors

Yang Ye¹, Qian Yang¹, Jinling Wei¹, Chenxi Shen¹, Haixing Wang¹, Rong Zhuang¹, Yuan Cao¹, Yajun Ding¹, Haoran Xu¹, Shuyang Xiang¹, Hongxia Mei¹, Zhongwang Li¹, Xiya Ren², Chen Zhang², Ji Xiao¹, Shengxing Zheng¹, Ting Li¹, Ruifeng Zeng¹, Huacheng Liu¹, Han Lin¹, Wangning Shang-Guan¹, Ming Li³, Shengwei Jin⁴, Qian Wang⁵

Affiliations

¹ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China.
² Wenzhou Medical University, Wenzhou, People's Republic of China.
³ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China.
⁴ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China. Electronic address: jsw@wmu.edu.cn.
⁵ Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China. Electronic address: wqian84@163.com.

PMID: 38237770
DOI: 10.1016/j.jare.2024.01.017

Abstract

Introduction: Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear.

Objectives: Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS.

Methods: Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry.

Results: RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9^-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher.

Conclusions: We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.

Keywords: Acute respiratory distress syndrome; Resident alveolar macrophages; Resolution of inflammation; Resolvin D1; S100A8/A9.