The Role of the Actin‐Binding Protein Cortactin in the Onset and Development of Sepsis

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IntroductionSepsis is a devastating disease, which occurs as a result of an exacerbated immune response to systemic infection. Major hallmarks of sepsis include increased vascular permeability and leukocyte recruitment to secondary organs such as lung and kidney, often leading to organ dysfunction and, in severe cases, organ failure. Cortactin is an actin‐binding protein, expressed ubiquitously with the exception of neutrophils. Endothelial cortactin regulates vascular permeability and neutrophil recruitment by controlling activation of small GTPases. Therefore, endothelial cortactin could play an important role during sepsis pathogenesis by controlling neutrophil influx into affected organs such as lungs.Aim/ObjectiveTo elucidate the effects of cortactin deficiency on the onset and development of sepsis, which is a disease characterized by massive systemic neutrophil extravasation.Experimental StrategySepsis was induced by cecal ligation and puncture (CLP) in age‐matched male cortactin‐deficient (CTTN KO) and littermate wild‐type (WT) mice; and five day survival was monitored. Blood and lung tissue samples were collected 24 h after CLP for protein and gene expression analysis. Lung histology was analyzed after hematoxylin/eosin staining of paraffin‐crossections of lung tissue. Oxidative stress was assessed in lung cross‐sections using dihydroethidium. mRNA and protein levels of inflammatory cytokines were assessed by quantitative real‐time PCR (lung tissue) and bead‐based milliplex assay (peripheral blood) respectively. Neutrophil numbers were determined in blood and peritoneum by flow cytometry.Results and ConclusionsCortactin deficiency improved survival of mice subjected to CLP. Of note, lung tissue of septic KO animals showed better preserved architecture of the alveoli, and absence of oedema, hemorrhage and mucus deposition. Gene expression and secretion of the inflammatory mediators tumor necrosis factor‐α (TNFα) and interleukin‐1β in KO mice were reduced in comparison to septic WT mice. Moreover, we observed less oxidative stress in the lungs of septic KO mice in comparison to septic WT mice. Cortactin deficiency also protected against sepsis‐induced neutropenia. Additionally, in the absence of cortactin, less neutrophils were recruited to the peritoneum without compromising bacterial clearance. In summary, cortactin deficiency attenuates both local and systemic inflammatory responses during sepsis, protects against sepsis‐induced neutropenia and protects from lung tissue damage. Thus, cortactin could be an interesting target as novel treatment strategy for sepsis.Cortactin deficiency protects against sepsis‐induced lung damageFigure 1Expression of inflammatory cytokines in the lung are reduced in the absence of cortactinFigure 2