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

J Adv Res. 2025 Jan:67:289-299. doi: 10.1016/j.jare.2024.01.017. Epub 2024 Jan 17.

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.

MeSH terms

  • Animals
  • Calgranulin A* / metabolism
  • Calgranulin B* / metabolism
  • Cell Self Renewal
  • Disease Models, Animal
  • Docosahexaenoic Acids* / metabolism
  • Docosahexaenoic Acids* / pharmacology
  • Female
  • Humans
  • Lipopolysaccharides
  • Macrophages, Alveolar* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phagocytosis
  • Receptors, Formyl Peptide / metabolism
  • Receptors, Lipoxin / metabolism
  • Respiratory Distress Syndrome* / metabolism
  • Signal Transduction

Substances

  • resolvin D1
  • Calgranulin B
  • Docosahexaenoic Acids
  • Calgranulin A
  • Receptors, Lipoxin
  • S100A9 protein, mouse
  • S100A9 protein, human
  • S100a8 protein, mouse
  • Lipopolysaccharides
  • Receptors, Formyl Peptide