Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Front Immunol. 2022 Sep 15;13:953530. doi: 10.3389/fimmu.2022.953530. eCollection 2022.
Innate immunity is a primary defense system against microbial infections. Innate immune pattern recognition receptors (PRRs) play pivotal roles in detection of invading pathogens. When pathogens, such as bacteria and viruses, invade our bodies, their components are recognized by PRRs as pathogen-associated molecular patterns (PAMPs), activating the innate immune system. Cellular components such as DNA and RNA, acting as damage-associated molecular patterns (DAMPs), also activate innate immunity through PRRs under certain conditions. Activation of PRRs triggers inflammatory responses, interferon-mediated antiviral responses, and the activation of acquired immunity. Research on innate immune receptors is progressing rapidly. A variety of these receptors has been identified, and their regulatory mechanisms have been elucidated. Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) constitute a major family of intracellular PRRs and are involved in not only combating pathogen invasion but also maintaining normal homeostasis. Some NLRs are known to form multi-protein complexes called inflammasomes, a process that ultimately leads to the production of inflammatory cytokines and induces pyroptosis through the proteolytic cascade. The aberrant activation of NLRs has been found to be associated with autoimmune diseases. Therefore, NLRs are considered targets for drug discovery, such as for antiviral drugs, immunostimulants, antiallergic drugs, and autoimmune disease drugs. This review summarizes our recent understanding of the activation and regulation mechanisms of NLRs, with a particular focus on their structural biology. These include NOD2, neuronal apoptosis inhibitory protein (NAIP)/NLRC4, NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, and NLRP9. NLRs are involved in a variety of diseases, and their detailed activation mechanisms based on structural biology can aid in developing therapeutic agents in the future.
先天免疫系统是抵御微生物感染的主要防御系统。先天免疫模式识别受体（PRRs）在检测入侵病原体方面发挥着关键作用。当细菌和病毒等病原体侵入我们的身体时，PRRs 会识别它们的成分作为病原体相关分子模式（PAMPs），从而激活先天免疫系统。在某些条件下，细胞成分（如 DNA 和 RNA）作为损伤相关分子模式（DAMPs），也可以通过 PRRs 激活先天免疫。PRRs 的激活会引发炎症反应、干扰素介导的抗病毒反应和获得性免疫的激活。先天免疫受体的研究进展迅速。已经鉴定出多种此类受体，并阐明了它们的调节机制。核苷酸结合和寡聚结构域（NOD）样受体（NLRs）构成了细胞内 PRR 的主要家族，不仅参与抵御病原体入侵，还参与维持正常的体内平衡。一些 NLRs 已知会形成称为炎性小体的多蛋白复合物，这一过程最终导致炎症细胞因子的产生，并通过蛋白水解级联诱导细胞焦亡。已经发现 NLRs 的异常激活与自身免疫性疾病有关。因此，NLRs 被认为是药物发现的靶点，例如抗病毒药物、免疫刺激剂、抗过敏药物和自身免疫性疾病药物。本综述总结了我们对 NLRs 的激活和调节机制的最新理解，特别关注其结构生物学。这些包括 NOD2、神经元凋亡抑制蛋白（NAIP）/NLRC4、NLR 家族包含吡啶结构域蛋白 1（NLRP1）、NLRP3、NLRP6 和 NLRP9。NLRs 参与多种疾病，其基于结构生物学的详细激活机制可以帮助未来开发治疗药物。
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