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Fibronectin extra domain a limits liver dysfunction and protects mice during acute inflammation()
BACKGROUND AND AIM: The primary transcript of fibronectin (FN) undergoes alternative splicing to generate different isoforms, including FN containing the Extra Domain A (FN_EDA+), whose expression is regulated spatially and temporarily during developmental and disease conditions including acute infl...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10242638/ https://www.ncbi.nlm.nih.gov/pubmed/37287804 http://dx.doi.org/10.1016/j.athplu.2023.05.002 |
Sumario: | BACKGROUND AND AIM: The primary transcript of fibronectin (FN) undergoes alternative splicing to generate different isoforms, including FN containing the Extra Domain A (FN_EDA+), whose expression is regulated spatially and temporarily during developmental and disease conditions including acute inflammation. The role of FN_EDA+ during sepsis, however, remains elusive. METHODS: Mice constitutively express the EDA domain of fibronectin (EDA(+/+)); lacking the FN EDA domain (EDA(−/−)) or with a conditional ablation of EDA + inclusion only in liver produced FN (alb-CRE(+)EDA floxed mice) thus expressing normal plasma FN were used. Systemic inflammation and sepsis were induced by either LPS injection (70 mg/kg) or by cecal ligation and puncture (CLP) Neutrophils isolated from septic patients were tested for neutrophil binding ability. RESULTS: We observed that EDA(+/+) were protected toward sepsis as compared to EDA(−/−) mice. Also alb-CRE(+)EDA floxed mice presented reduced survival, thus indicating a key role for EDA in protecting toward sepsis. This phenotype was associated with improved liver and spleen inflammatory profile. Ex vivo experiments showed that neutrophils bind to a larger extent to an FN_EDA + coated surface as compared to FN, thus potentially limiting their over-reactivity. CONCLUSIONS: Our study demonstrates that the inclusion of the EDA domain in fibronectin dampens the nflammatoryi consequences of sepsis. |
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