IL-36R signaling integrates innate and adaptive immune-mediated protection against enteropathogenic bacteria.
IL-36R signaling integrates innate and adaptive immune-mediated protection against enteropathogenic bacteria.
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IL-36R 信号传导整合了先天性和适应性免疫介导的针对肠道致病细菌的保护。
DOI：
10.1073/pnas.2004484117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Denning,TimothyL
中科院分区：
文献类型：
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作者：
Ngo,VuL;Abo,Hirohito;Kuczma,Michal;Szurek,Edyta;Moore,Nora;Medina-Contreras,Oscar;Nusrat,Asma;Merlin,Didier;Gewirtz,AndrewT;Ignatowicz,Leszek;Denning,TimothyL
肠道病原性细菌感染是一个全球性的健康问题，与高死亡率有关，特别是在发展中国家。免疫细胞和非免疫细胞之间的协调反应是宿主对肠道致病性细菌感染的有效保护的特征。在对小鼠感染的应答中，先天免疫细胞被激活以产生白细胞介素（IL）-23和IL-22，其促进抗菌肽（AMP）的产生和细菌清除。IL-36细胞因子是促炎性IL-1超家族成员，但它们在肠道致病性细菌感染中的作用仍不清楚。使用肠道小鼠病原体，啮齿类梭菌，我们证明了通过IL-36受体（IL-36 R）的信号转导协调了一个关键的先天适应性免疫连接，以控制细菌感染。IL-36 R缺陷小鼠（Il 1 rl 2 −/−）表现出IL-22和AMP表达的显著受损，肠道损伤增加，并且未能包含C。与对照组相比。这些缺陷与未能诱导IL-23和IL-6相关，IL-23和IL-6分别是感染早期和晚期的两种关键IL-22诱导剂。在C.啮齿动物感染挽救了第3组先天性淋巴细胞（ILC）产生IL-22，而在晚期阶段给予IL-6挽救了CD 4 +T细胞产生IL-22介导的IL-22，两种治疗都保护了Il 1 rl 2 −/−小鼠免受非包容性感染。此外，IL-36 R介导的CD 4 +T细胞产生IL-22依赖于树突状细胞（DC）中NFκB-p65和IL-6的表达，以及CD 4 +T细胞的芳烃受体（AhR）表达。总的来说，这些数据表明IL-36信号传导途径整合了先天性和适应性免疫，导致宿主防御肠道病原性细菌感染。
Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen,C.rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2−/−) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to containC. rodentiumcompared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment ofIl1rl2−/−mice with IL-23 during the early phase ofC. rodentiuminfection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4+T cell, and both treatments protectedIl1rl2−/−mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4+T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4+T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.