Abstract
Functionally compromised neutrophils contribute to adverse clinical outcomes in patients with severe inflammation and injury such as colitis and sepsis. However, the ontogeny of dysfunctional neutrophil during septic colitis remain poorly understood. We report that the dysfunctional neutrophil may be derived by the suppression of Toll-interacting-protein (Tollip). We observed that Tollip deficient neutrophils had compromised migratory capacity toward bacterial product fMLF due to reduced activity of AKT and reduction of FPR2, reduced potential to generate bacterial-killing neutrophil extra-cellular trap (NET), and compromised bacterial killing activity. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. The inflamed and incompetent neutrophil phenotype was also observed in vivo in Tollip deficient mice subjected to DSS-induced colitis. We observed that TUDCA, a compound capable of restoring Tollip cellular function, can potently alleviate the severity of DSS-induced colitis. In humans, we observed significantly reduced Tollip levels in peripheral blood collected from human colitis patients as compared to blood samples from healthy donors. Collectively, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.
Highlights
Its homeostatic function through facilitating autophagy completion[11]
Our data reveal that Tollip deficiency skews the programming of inflamed yet incompetent neutrophils that underlie the pathogenesis of acute injury and septic colitis in mice and humans
Neutrophils from Tollip deficient mice subjected to Dextran Sulfate Sodium (DSS)-induced septic colitis exhibited heightened inflammatory responses such as elevated levels CCR5, and increased secretion of MPO
Summary
Its homeostatic function through facilitating autophagy completion[11]. Suppression of Tollip through reduced expression or altered cellular localization may lead to disrupted autophagy, cellular stress and inflammation[11]. We demonstrated that Tauroursodeoxycholic Acid (TUDCA), a potent compound in relieving cellular stress, can effectively enhance the homeostatic function of Tollip through maintaining its proper lysosome localization and expression[11]. Despite these intriguing studies, the potential roles of Tollip in neutrophils remain unknown. We utilized the murine DSS septic colitis model to test the hypothesis that Tollip deficiency may exacerbate DSS colitis through polarizing “inflamed yet incompetent” neutrophils, inciting tissue inflammation, and compromising host anti-microbial defense. The levels of Tollip in human blood neutrophils collected from patients with acute colitis were determined
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