Pep27 Mutant Immunization Inhibits Caspase-14 Expression to Alleviate Inflammatory Bowel Disease via Treg Upregulation

Abstract

Inflammatory bowel disease (IBD) is a highly prevalent gut inflammatory disorder. Complicated clinical outcomes prolong the use of conventional therapy and often lead to compromised immunity followed by adverse events and high relapse rates. Thus, a profound medical intervention is required. Previously, intranasal immunization of pneumococcal pep27 mutant (Δpep27) exhibited long-lasting protection against immune-related disorders. System biology analysis has predicted an inverse correlation between Δpep27 immunization and gastroenteritis. Recently, we established that Δpep27-elicited Tregs repressed Wnt5a expression and enhanced barrier integrity, suggesting the restoration of immunological tolerance. Therefore, we evaluated whether Δpep27 can alleviate IBD. Δpep27 dose-dependent response was analyzed in dextran sulfate sodium-induced mice using transcriptome analysis. Pro- and anti-inflammatory signatures were cross-correlated by quantitative PCR and western blot analyses. To address the hierarchy regulating the activity of caspase-14, an undefined marker in IBD, and regulatory T cells (Tregs), antibody-based neutralization studies were conducted. Fecal microbiome profiles were analyzed by 16S rRNA pyrosequencing. Δpep27 significantly attenuated dextran sulfate sodium-induced oxidative stress parameters, proinflammatory cytokines, caspase-14 expression level, and upregulated tight junction, anti-inflammatory genes IL-10 and TGF-β1 via upregulation of Tregs to restore healthy gut microbiota. Neutralization studies unveiled that ∆pep27 had a remedial effect via Treg upregulation. Caspase-14, being an important mediator in the pathogenesis of IBD, can be an alternate therapeutic target in IBD. ∆pep27-increased Tregs repressed caspase-14 expression and reversed gut microbial dysbiosis, aiding to re-establish immunological tolerance.

Intranasal Immunization of Pneumococcal pep27 Mutant Attenuates Allergic and Inflammatory Diseases by Upregulating Skin and Mucosal Tregs

“…Additionally, SCFA are known to limit mucosal inflammation by the induction of Tres [24]. Our findings indicates that microbiota composition in Δpep27-immunizaed colitis mice showed positive correlations with the Treg induction and negative association with the proinflammatory cytokines [25].…”

“…During our approach to intranasal immunization using Δpep27 for prevention of pneumococcal diseases, microarray and system biology analyses of human lung cells after a Δpep27 infection unraveled unexpected features predicting preventive effect of influenza virus infection and intestinal abnormality. Thereafter, a series of experiments on this prediction were performed and show that the prediction is true [25,36,37].…”

“…Inhibition of Treg function confirmed that ∆pep27 has therapeutic effects on gut inflammation and caspase-14 via Treg upregulation. Overall, intranasal immunization with ∆pep27 can attenuate colonic inflammation via Treg induction and could be a highly pragmatic way to re-establish immunological tolerance [25,36] (Figure 1).…”

SPRR3 as a diagnostic and prognostic molecular marker for lung adenocarcinoma based on pan-cancer analysis

“…Caspase-14 belongs to caspase family that is related to apoptosis. Many previous studies have shown that caspase has an important effect on pathology of various disorders, like retinal dysfunction and multiple malignant tumors [33][34].…”