Gasdermin D in macrophages drives orchitis by regulating inflammation and antigen presentation processes.

Inflammation in the testes induced by infection and autoimmunity contributes significantly to male infertility, a public health issue. Current therapies using antibiotics and broad-spectrum anti-inflammatory drugs are ineffective against non-bacterial orchitis and induce side effects. This highlights the need to explore the pathogenesis of orchitis and develop alternative therapeutic strategies. In this study, we demonstrated that Gasdermin D (GSDMD) was activated in the testes during uropathogenic Escherichia coli (UPEC)-induced acute orchitis, and that GSDMD in macrophages induced inflammation and affected spermatogenesis during acute and chronic orchitis. In testicular macrophages, GSDMD promoted inflammation and antigen presentation, thereby enhancing the T-cell response after orchitis. Furthermore, the pharmacological inhibition of GSDMD alleviated the symptoms of UPEC-induced acute orchitis. Collectively, these findings provide the first demonstration of GSDMD's role in driving orchitis and suggest that GSDMD may be a potential therapeutic target for treating orchitis. Synopsis: Inflammation in the testis triggered by infection or an autoimmune disorder may lead to male infertility. Uropathogenic Escherichia coli (UPEC)-induced orchitis and experimental autoimmune orchitis (EAO) mouse models were used to identify the critical role of the Gasdermin D (GSDMD)-mediated pyroptosis in the pathogenesis of orchitis. The cleavage of GSDMD in testis is induced by UPEC infection. Gsdmd^fl/flCx3cr1-cre mice are protected from UPEC-induced acute orchitis and chronic EAO. GSDMD deficiency reduces inflammatory response and antigen presentation capacities of macrophages, thereby impairing CD8 + T-cell response. The FDA-approved drug DMF inhibiting GSDMD activation alleviates UPEC-induced acute orchitis. Inflammation in the testis triggered by infection or an autoimmune disorder may lead to male infertility. Uropathogenic Escherichia coli (UPEC)-induced orchitis and experimental autoimmune orchitis (EAO) mouse models were used to identify the critical role of the Gasdermin D (GSDMD)-mediated pyroptosis in the pathogenesis of orchitis. [ABSTRACT FROM AUTHOR]