Post-septic hosts exhibit altered lung immunity, leading to increased susceptibility to bacterial pneumonia. Epithelial cells can attract immune cells to the lung upon injury. Phagocytic cells are essential to epithelial wound healing by clearing debris, regulating inflammation, and promoting tissue repair. Our team showed that TLR2 acts as a susceptibility factor to secondary bacterial pneumonia in a murine model of polymicrobial peritonitis [1Pène F., Grimaldi D., Zuber B., Sauneuf B., Rousseau C., El Hachem C., et al. Toll-Like Receptor 2 Deficiency Increases Resistance to Pseudomonas aeruginosa Pneumonia in the Setting of Sepsis-Induced Immune Dysfunction The Journal of Infectious Diseases 2012 ;  206 : 932-942

Cliquez ici pour aller à la section Références]. We also demonstrated that sepsis induces TLR2-dependent bronchial epithelial morphological and functional alterations including dysplasia [2Malherbe J., Friol A., Rousseau C., Dauriat C., Péju E., Llitjos J.F., et al. Involvement of bronchial epithelium in sepsis-induced immunosuppression Rev Mal Respir 2023 ;  40 : 131-132 [cross-ref]

Cliquez ici pour aller à la section Références]. Hence, we hypothesized that sepsis might induce dysfunction of the bronchial epithelium ability to recruit and activate phagocytic immune cells.

C57BL/6J female mice were subjected to polymicrobial peritonitis induced by cecal ligation and puncture (CLP) or control sham surgery. Quantity and localisation of polynuclear neutrophils and macrophages were studied by immunohistochemistry at day 7 after surgery, prior to any secondary bacterial challenge.

As compared to sham-operated mice, post-septic mice showed a significant decrease of whole lung and of epithelial-associated macrophages (median epithelial-associated macrophages staining ratio was 5.3% for septic mice compared to 2,2% for the controls, P=0,048). No increase in epithelial-associated polynuclear neutrophils was observed despite a significant overall lung infiltration (median epithelial-associated neutrophils staining ratio 1,484% for septic mice compared to 0,7151% for the controls, P=0,2571). Conversely, tlr2-/- post septic mice exhibited a significant increase of whole lung and epithelial-associated macrophages and polynuclear neutrophils in comparison with tlr2-/- control mice (median epithelial-associated macrophages staining ratio 6.726% for septic mice compared to 3,270% for the controls, P=0,0159; median epithelial associated neutrophils staining ratio 6,530% for septic mice compared to 2,665% for the controls, P=0.0159).

Our data show a TLR2-dependent defect in epithelial-recruitment of phagocytes post sepsis. These results suggest a crucial role of phagocytes in previously observed sepsis-induced alteration in epithelial morphology and functions (e.g. epithelial dysplasia) which may contribute to the increased susceptibility of post-septic hosts to secondary pneumonia. Further ex vivo experiments using primary air-liquid interface epithelial cultures from WT and tlr2-/- post-septic mice will allow us to identify the contribution of epithelial and immune TLR2 signalling in these alterations.