Loss of Interleukin-10 (IL-10) Signaling Promotes IL-22-Dependent Host Defenses against Acute Clostridioides difficile Infection.

Infection with the bacterial pathogen causes severe damage to the intestinal epithelium that elicits a robust inflammatory response. Markers of intestinal inflammation accurately predict clinical disease, however, the extent to which host-derived proinflammatory mediators drive pathogenesis versus promote host protective mechanisms remains elusive. In this report, we employed mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, on disease pathogenesis. Upon challenge, mice exhibited significantly decreased morbidity and mortality compared to littermate heterozygote () control mice, despite a comparable burden, innate immune response, and microbiota composition following infection. Similarly, antibody-mediated blockade of interleukin-10 (IL-10) signaling in wild-type C57BL/6 mice conveyed a survival advantage if initiated 3 weeks prior to infection. In contrast, no advantage was observed if blockade was initiated on the day of infection, suggesting that the constitutive activation of inflammatory defense pathways prior to infection mediated host protection. IL-22, a cytokine critical in mounting a protective response against infection, was elevated in the intestine of uninfected, antibiotic-treated mice, and genetic ablation of the IL-22 signaling pathway in mice negated the survival advantage following challenge. Collectively, these data demonstrate that constitutive loss of IL-10 signaling, via genetic ablation or antibody blockade, enhances IL-22-dependent host defense mechanisms to limit pathogenesis.