IL-23/IL23R promote macrophage pyroptosis and Th1/Th17 cell differentiation in mycobacterial infection.
IL-23/IL23R promote macrophage pyroptosis and Th1/Th17 cell differentiation in mycobacterial infection.
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DOI：
10.1016/j.jid.2023.04.019
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发表时间：
2023-05
期刊：
影响因子：
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通讯作者：
Chuan Wang;Tingting Liu;Zhenzhen Wang;Wenchao Li;Qing Zhao;Z. Mi;Xiaotong Xue;Peidian Shi
中科院分区：
文献类型：
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作者：
Chuan Wang;Tingting Liu;Zhenzhen Wang;Wenchao Li;Qing Zhao;Z. Mi;Xiaotong Xue;Peidian Shi
病原体诱导的表观遗传修饰可以重塑抗感染免疫过程，控制宿主反应的幅度。DNA甲基化图谱已经确定了与疾病相关的关键异常甲基化变化，从而为表观遗传因素在分枝杆菌感染中的作用提供了生物学见解。在这项研究中，我们对麻风病患者和健康对照的皮肤活检组织进行了全基因组甲基化分析。功能浓缩分析发现T辅助分子17分化途径与麻风显著相关。根据DNA甲基化、RNA测序和GWASS的综合分析，IL-23R作为这一途径中的关键基因，被发现在麻风分枝杆菌免疫中起关键作用。功能分析表明，IL-23/IL-23R−通过激活Caspase-1/GSDMD介导的巨噬细胞内依赖于NLRP3的信号转导和转录激活子3信号通路，促进细菌清除。IL23/IL-23R可促进T辅助细胞1和T辅助17细胞分化和促炎细胞因子的分泌，从而增强宿主杀菌活性。IL-23R基因敲除可减弱上述影响并增加对分枝杆菌感染的易感性。这些发现阐明了IL-23/IL-23R在调节巨噬细胞内细菌清除方面的生物学功能，并进一步支持了它们在T辅助细胞分化中的调节作用。我们的研究强调，IL-23/IL-23R可能成为预防和治疗麻风和其他分枝杆菌感染的潜在靶点。
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. In this study, we performed a genome-wide methylation analysis of skin biopsies from patients with leprosy and healthy controls. T helper 17 differentiation pathway was found to be significantly associated with leprosy through functional enrichment analysis. As a key gene in this pathway,IL-23Rwas found to be critical to mycobacterial immunity in leprosy, according to integrated analysis with DNA methylation, RNA sequencing, and GWASs. Functional analysis revealed that IL-23/IL-23R−enhanced bacterial clearance by activating caspase-1/GSDMD-mediated pyroptosis in a manner dependent on NLRP3 through signal transducer and activator of transcription 3 signaling in macrophages. Moreover, IL23/IL-23R promoted T helper 1 and T helper 17 cell differentiation and proinflammatory cytokine secretion, thereby increasing host bactericidal activity. IL-23R knockout attenuated the effects and increased susceptibility to mycobacterial infection mentioned earlier. These findings illustrate the biological functions of IL-23/IL-23R in modulating intracellular bacterial clearance in macrophages and further support their regulatory effects in T helper cell differentiation. Our study highlights that IL-23/IL-23R might serve as potential targets for the prevention and treatment of leprosy and other mycobacterial infections.