School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
School of Biological Sciences, University of Missouri - Kansas City, Kansas City, MO, 64110-2499, USA.
Mol Immunol. 2019 Mar;107:142-164. doi: 10.1016/j.molimm.2018.12.024. Epub 2019 Feb 8.
Immune sensing of exogenous molecules from microbes (e.g., pathogen-associated molecular patterns) and nonmicrobial molecules (e.g., asbestos, alum, and silica), as well as endogenous damage-associated molecular patterns (e.g., ATP, uric acid crystals, and amyloid A) activates innate immunity by inducing immune-related genes, including proinflammatory cytokines, which further facilitate the development of adaptive immunity. The roles of transcriptional responses downstream of immune sensing have been widely characterized in informing adaptive immunity; however, few studies focus on the effect of post-translational responses on the modulation of adaptive immune responses. Inflammasomes activated by the previously described endo- and exogenous stimuli autocatalytically induce intracellular pro-caspase-1, which cleaves the inactive precursors of interleukin-1β (IL-1β) and IL-18 into bioactive proinflammatory cytokines. IL-1β and IL-18 not only contribute to the host defense against infections by activating phagocytes, such as monocytes, macrophages, dendritic cells, and neutrophils, but also induce T-helper 17 (Th17)- and Th1-mediated adaptive immune responses. In synergy with IL-6 and IL-23, IL-1β activates IL-1 receptor (IL-1R) signaling to drive the differentiation of IL-17-producing Th17 cells, which not only play critical roles in host protective immunity to infections of bacteria, fungi, and certain viruses but also participate in the pathology of inflammatory disorders and tumorigenesis. Consequently, targeting inflammasomes and IL-1/IL-1R signaling may effectively improve the treatment of Th17-associated disorders, such as autoinflammatory diseases and cancers, thereby providing novel insights into drug development.
外源性分子（例如，病原体相关分子模式）和非微生物分子（例如，石棉、明矾和二氧化硅）以及内源性损伤相关分子模式（例如，ATP、尿酸晶体和淀粉样蛋白 A）的免疫感应，以及非微生物分子（例如，石棉、明矾和二氧化硅）的免疫感应，通过诱导免疫相关基因，包括促炎细胞因子，从而激活先天免疫，这进一步促进了适应性免疫的发展。免疫感应下游的转录反应在告知适应性免疫方面的作用已经得到了广泛的描述；然而，很少有研究关注翻译后反应对适应性免疫反应调节的影响。以前描述的内源性和外源性刺激物激活的炎性小体通过自动催化诱导细胞内原胱天蛋白酶-1 的活化，将白细胞介素-1β（IL-1β）和白细胞介素-18 的无活性前体切割成生物活性的促炎细胞因子。IL-1β 和 IL-18 不仅通过激活吞噬细胞（如单核细胞、巨噬细胞、树突状细胞和中性粒细胞）来帮助宿主抵抗感染，还诱导辅助性 T 细胞 17（Th17）和 Th1 介导的适应性免疫反应。与 IL-6 和 IL-23 协同作用，IL-1β 激活 IL-1 受体（IL-1R）信号通路，驱动 IL-17 产生的 Th17 细胞的分化，这不仅在宿主对细菌、真菌和某些病毒感染的保护性免疫中发挥关键作用，而且还参与炎症性疾病和肿瘤发生的病理过程。因此，靶向炎性小体和 IL-1/IL-1R 信号通路可能有效地改善 Th17 相关疾病（如自身炎症性疾病和癌症）的治疗效果，从而为药物开发提供新的思路。
