Progranulin protects against Clostridioides difficile infection by enhancing IL-22 production
Jun Huang,
Bichen Liu,
Yi Liu,
Wenxian You,
Ping Zhao,
Yuhan Liu,
Kehan Wang,
Xiaofei Lai,
Banglao Xu,
Ju Cao
Affiliations
Jun Huang
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Bichen Liu
Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China
Yi Liu
Department of Surgery, School of Medicine, Stanford University, Stanford, USA
Wenxian You
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Ping Zhao
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Yuhan Liu
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Kehan Wang
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Xiaofei Lai
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Banglao Xu
Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
Ju Cao
Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Enhanced mortality, relapse rates, and increased prevalence of Clostridioides difficile 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 ex vivo. 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.
