Claudin 4 is a tight junction protein that plays a significant role in maintaining permeability in the gut and lung epithelia. Considering the importance of intestinal and pulmonary leak in the pathophysiology of critical illness, this study aimed to investigate the significance of claudin 4 in sepsis. Wild-type (WT) and mice with a germline deletion of claudin 4 were subjected to intraabdominal sepsis and either sacrificed at pre-determined timepoints or followed 7 days for survival. Intestinal permeability through the pore and leak pathways was significantly decreased in claudin 4 -/- mice at 24 hours (pore and leak) and 48 hours (pore) whereas the unrestricted pathway was unaffected. Consistent with changes in permeability to small molecules but not larger molecules, IL-6 and IL-10 were significantly decreased in claudin 4 -/- mice at 24 hours whereas there was no difference in systemic bacterial burden. Splenic flow cytometry demonstrated a higher frequency of effector memory phenotype CD4 + T cells and CD8 + T cells as well as a lower frequency of Helios + and CTLA-4 + CD4 + Foxp3 + Regulatory T cells subpopulations in claudin 4 -/- mice at 24 hours. Locally, enterocyte proliferation was higher and intestinal epithelial migration was more rapid in claudin 4 -/- mice with decreased IL-6 and IL-10 in jejunal mucosal tissue at 24 hours. Despite known expression of claudin 4 in the lung, lung epithelial and endothelial permeability were both unchanged in claudin 4 -/- mice without changes in pulmonary wet-to-dry ratio or lung myeloperoxidase activity at 24 hours. Notably, claudin 4 -/- mice had markedly improved 7-day survival following sepsis. Claudin 4 thus appears to play a detrimental role in sepsis pathology, potentially mediated through intestinal permeability leading to worsened systemic inflammation. Targeting claudin 4 therefore represents a potential therapeutic strategy in sepsis.
Shimazui et al. (2026) studied this question.