Pneumococcal pep27-mutant inhibits Wnt5a expression via the regulation of T helper cells to attenuate colitis.

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic gut inflammatory disease characterized by extensive colitis and remission of the symptoms. The incidence rate and prevalence of IBD are increasing worldwide; IBD affects millions of people, has poorly defined etiology, and often results in a failure of pharmacological interventions. Regardless of the cause, mucosal healing is indispensable for the regeneration of inflamed mucosa to ensure intestinal homeostasis. Intranasal immunization with the pneumococcal pep27 mutant (Δpep27) has been reported as an avirulent and live vaccine that has been proposed to suppress immune-regulated disorders, eliciting long-lasting immunity. The dose-dependent activity of Δpep27 in the lungs was measured by transcriptome analysis to investigate the long-lasting immunogenic response against IBD. Novel therapeutic targets based on the modulation of Wnt signaling and T regulatory cells interconnected with other signaling cascades in the context of IBD were investigated by qPCR and immunoblotting. M1/M2 macrophages were quantified by FACS analysis. Dextran sulfate sodium-induced colitis induced significant upregulation of Th2 and Th17 as well as noncanonical Wnt5, which subsequently inhibited regulatory T (Treg) expression. In contrast, Δpep27 immunization significantly attenuated the levels of Wnt5, proinflammatory cytokines, oxidative stress parameters, and infiltration of inflammatory cells and enhanced barrier integrity via T helper cell homeostasis and upregulation of M2 macrophages. The data of the present study suggested that Δpep27-elicited Tregs were able to repress Wnt5a expression, assisting with the restoration of immunological tolerance and providing a robust regenerative and antioxidant milieu.