IL-23/IL-23R Promote Macrophage Pyroptosis and T Helper 1/T Helper 17 Cell Differentiation in Mycobacterial Infection

Pathogen-induced epigenetic modifications can reshape anti-infection immune processes and control the magnitude of host responses. DNA methylation profiling has identified crucial aberrant methylation changes associated with diseases, thus providing biological insights into the roles of epigenetic factors in mycobacterial infection. Here, we performed a genome-wide methylation analysis of skin biopsies from patients with leprosy and healthy controls. The Th17 differentiation pathway was found to be significantly associated with leprosy through functional enrichment analysis. As a key gene in this pathway, IL23R was found to be critical to mycobacterial immunity in leprosy, according to integrated analysis with DNA methylation, RNA sequencing and genome-wide association studies. Functional analysis revealed IL-23/IL23R enhanced bacterial clearance by activating caspase-1/GSDMD-mediated pyroptosis in a manner dependent on NLRP3 through STAT3 signaling in macrophages. Moreover, IL23/IL23R promoted Th1 and Th17 cell differentiation and proinflammatory cytokine secretion, thereby increasing host bactericidal activity. IL23R knockout attenuated the aforementioned effects and increased susceptibility to mycobacterial infection. These findings illustrate biological functions of IL-23/IL23R in modulating intracellular bacterial clearance in macrophages and further support their regulatory effects in Th cell differentiation. Our study highlights IL-23/IL23R might serve as potential targets for the prevention and treatment of leprosy and other mycobacterial infections.