Osteopontin Depletion in Non-haematopoietic Cells Improves Outcomes in Septic Mice by Enhancing Antimicrobial Peptide Production.

ABSTRACT

Osteopontin (Opn) depletion can improve septic outcomes, but the underlying mechanism remains unknown. In this study, we demonstrated that non-haematopoietic but not haematopoietic Opn depletion improved septic outcomes. Compared to wild-type (WT) mice, co-housed Opn-/- mice displayed enhanced production of antibacterial peptides (AMPs), decreased bacterial loads, and a distinct bacterial composition of gut microbiota. Fecal microbiota transplantation (FMT) and OPN neutralization assay showed that Opn depletion could reduce the bacterial loads and improve septic inflammation. By employing an intestinal organoid culture system, we proved that OPN neutralization in WT organoids could inactivate AKT and decrease FOXO3a phosphorylation, resulting in enhanced AMP production, whereas OPN treatment in OPN deficient organoids could activate AKT and increase FOXO3a phosphorylation, leading to reduced AMP production. Our findings identified OPN as a novel regulatory factor of AMP production to modulate bacterial loads and composition of gut microbiota, in turn affecting sepsis outcomes.