Annexin A3 Represses Endothelial Permeability and Inflammation During Sepsis via Actin Cytoskeleton Modulation.

Summary

Using ANXA3 knockout mice and HUVECs, the study shows that loss of ANXA3 worsens sepsis outcomes by increasing endothelial permeability through actin stress fiber formation and loss of junctional proteins. ANXA3 suppresses E-selectin via ATF2 signaling; actin polymerization inhibitors reverse barrier dysfunction, positioning ANXA3 as a protective regulator of endothelial integrity in sepsis.

Key Findings

• ANXA3 deficiency increased mortality, lung injury, leukocyte infiltration, and vascular permeability in sepsis models.
• Loss of ANXA3 induced actin stress fibers and reduced junction proteins (ZO-1, VE-cadherin, claudin-5), compromising barrier integrity.
• ANXA3 knockdown upregulated E-selectin via ATF2 phosphorylation, increasing monocyte adhesion; actin polymerization inhibitors reversed these effects.

Clinical Implications

While preclinical, the work suggests potential biomarker and therapeutic avenues—e.g., enhancing ANXA3 function or modulating actin dynamics—to reduce vascular leak and inflammation in sepsis.

Limitations

• Preclinical models (LPS/HUVEC) may not fully capture human sepsis heterogeneity.
• Sample size and blinding/randomization details are not specified in the abstract.

Future Directions

Validate ANXA3 as a prognostic/therapeutic target in clinical cohorts; develop small molecules or biologics to enhance ANXA3-mediated cytoskeletal stabilization.