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Blocking the ADAM9/ITGAV Pathway Ameliorates Sepsis-Induced Acute Lung Injury by Promoting Macrophage Efferocytosis
Long-Zhu Li1, Wan-Jie Gu1, Xiang-Kun Yuan1
1Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Guangzhou, China.
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.
Insights
Inhibiting ADAM9 in macrophages improves acute lung injury (ALI) by enhancing the clearance of apoptotic neutrophils. Blocking the ADAM9-ITGAV interaction offers a potential therapeutic strategy for ALI.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Sepsis-induced acute lung injury (ALI) requires efficient clearance of apoptotic neutrophils.
- The mechanisms regulating macrophage efferocytosis in ALI are not fully understood.
Purpose of the Study:
- To investigate the role of ADAM9 in macrophage efferocytosis during sepsis-induced ALI.
- To explore the potential of targeting the ADAM9-ITGAV interaction for ALI treatment.
Main Methods:
- Lipopolysaccharide (LPS)-induced ALI mouse model.
- Inhibition of ADAM9 in macrophages and ITGAV in neutrophils.
- Analysis of bronchoalveolar lavage fluid (BALF) for immune cells and cytokines.
- In vitro studies using bone marrow-derived macrophages (BMDMs) and apoptotic polymorphonuclear leukocytes (PMNs).
Main Results:
- Inhibiting ADAM9 in macrophages significantly ameliorated ALI in mice.
- ADAM9 inhibition reduced inflammatory cytokines (IFN-γ, iNOS) and increased anti-inflammatory cytokines (IL-4, IL-10).
- Downregulation of ADAM9 enhanced efferocytosis of PMNs by BMDMs, mediated by ADAM9 binding to ITGAV on PMNs.
Conclusions:
- ADAM9 plays a crucial role in regulating macrophage efferocytosis during sepsis-induced ALI.
- Targeting the interaction between ADAM9 and ITGAV presents a promising therapeutic approach for ALI.
