Loss of Interleukin-10 (IL-10) Signaling Promotes IL-22-Dependent Host Defenses against Acute Clostridioides difficile Infection [Host Response and Inflammation]

In this report, we employed Il10–/– mice as a model of spontaneous colitis to examine the impact of constitutive intestinal immune activation, independent of infection, on C. difficile disease pathogenesis. Upon C. difficile challenge, Il10–/– mice exhibited significantly decreased morbidity and mortality compared to littermate Il10 heterozygote (Il10HET) control mice, despite a comparable C. difficile 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 C. difficile infection, was elevated in the intestine of uninfected, antibiotic-treated Il10–/– mice, and genetic ablation of the IL-22 signaling pathway in Il10–/– mice negated the survival advantage following C. difficile 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 C. difficile pathogenesis.
Source: Infection and Immunity - Category: Infectious Diseases Authors: Tags: Host Response and Inflammation Source Type: research