02423nas a2200337   4500000000100000008004100001260001200042653002000054653001600074653002800090653001500118100001100133700001000144700001100154700000900165700001100174700000900185700001000194700001000204700001000214700001200224700001100236700001000247700001100257700001000268700001200278245010800290856007500398520159800473022001402071       2023                            d  c05/202310aDifferentiation10aIL-23/IL23R10aMycobacterial infection10apyroptosis1 aWang C1 aLiu T1 aWang Z1 aLi W1 aZhao Q1 aMi Z1 aXue X1 aShi P1 aSun Y1 aZhang Y1 aWang N1 aBao F1 aChen W1 aLiu H1 aZhang F00aIL-23/IL23R promote macrophage pyroptosis and Th1/Th17 cell differentiation in mycobacterial infection.  uhttps://www.jidonline.org/action/showPdf?pii=S0022-202X%2823%2902062-63 a<p>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.</p>
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