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

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.

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