Fibronectin extra domain a limits liver dysfunction and protects mice during acute inflammation

Abstract

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.