Progranulin protects against <i>Clostridioides difficile</i> infection by enhancing IL-22 production

Enhanced mortality, relapse rates, and increased prevalence of <i>Clostridioides difficile</i> infection (CDI) emphasize the need for better therapies and management approaches. Modulating host immune response to ameliorate CDI-associated immunopathology may provide new advantages to currently inadequate antibiotic therapies. Here, we identified progranulin (PGRN) as an important immune target upregulated in response to CDI. PGRN-deficient mice displayed dramatically higher mortality and aggravated epithelial barrier disruption compared with wild type (WT) mice after CDI despite equivalent levels of bacterial burden or toxin in the large intestine. Mechanistically, PGRN protection was mediated by IL-22 production from CD4⁺ T helper cells, as demonstrated by a decrease in colonic IL-22-producing CD4⁺ T helper cells in the intestine of PGRN-deficient mice upon CDI and a boost of IL-22-producing CD4⁺ T helper cells activated by PGRN <i>ex vivo</i>. Clinical evidence suggests that CDI patients had significantly higher serum levels of PGRN compared with healthy controls, which was significantly and positively correlated with IL-22. Our findings thus indicate a critical role for PGRN-promoted CD4⁺ T cell IL-22 production in shaping gut immunity and reestablishing the intestinal barrier during CDI. As an alternative to pathogen-targeted therapy, this study may provide a new host-directed therapeutic strategy to attenuate severe, refractory CDI.