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. 2025 Aug 15;39(15):e70845.
doi: 10.1096/fj.202501079R.

Blocking the ADAM9/ITGAV Pathway Ameliorates Sepsis-Induced Acute Lung Injury by Promoting Macrophage Efferocytosis

Long-Zhu Li  1 , Wan-Jie Gu  1 , Xiang-Kun Yuan  1 , Wai-Meng Fan  1 , Lu-Ming Zhang  1 , Zhong-Kai Qu  1 , Feng-Zhi Zhao  1 , Hai-Yan Yin  1
Affiliations

Blocking the ADAM9/ITGAV Pathway Ameliorates Sepsis-Induced Acute Lung Injury by Promoting Macrophage Efferocytosis

Long-Zhu Li et al. FASEB J. .

Abstract

Successfully inhibiting sepsis-induced acute lung injury (ALI) hinges on clearing apoptotic neutrophils; however, the underlying mechanisms of this process remain elusive. In the present study, we aim to investigate how ADAM9 regulates macrophage efferocytosis during ALI. In the lipopolysaccharide (LPS)-induced ALI mice, inhibiting ADAM9 in macrophages significantly improved ALI, simultaneously reducing the number of macrophages and neutrophils in BALF, along with a decrease in pro-inflammatory cytokines, including IFN-γ, iNOS, and an increase in IL-4, IL-10. In vitro, downregulation of ADAM9 expression in bone marrow-derived macrophages (BMDMs) improved macrophage efferocytosis to apoptotic polymorphonuclear leukocytes (PMNs). Besides, we demonstrated that ADAM9 in BMDMs could directly bind to ITGAV in PMNs; inhibiting ITGAV expression on PMNs effectively improved ADAM9-mediated macrophage efferocytosis. Blocking the interaction between ADAM9 and ITGAV may ameliorate sepsis-induced ALI by promoting macrophage efferocytosis.

Keywords: ADAM9; ITGAV; acute lung injury; efferocytosis; macrophage.

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