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 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.& COPY; 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study investigates the role of the Extra Domain A (EDA) of fibronectin in sepsis. Results show that mice with EDA expression are protected against sepsis, and neutrophils bind more to FN_EDA+ surface, potentially limiting over-reactivity.