BP Bioprocess 2164-5566 Scientific Research Publishing 10.12677/BP.2023.132015 BP-67475 BP20230200000_65294603.pdf 生命科学 RIPK2：治疗炎症性疾病的新靶点 RIPK2: A New Therapeutic Target for Inflammatory Diseases 赖 宇俊 2 1 郑 珩 2 1 中国药科大学生命科学与技术学院，江苏 南京 null 08 05 2023 13 02 105 114 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

炎症是机体受到刺激后出现的一种保护性反应，然而，失调的炎症反应又会引发各种炎症性疾病。受体相互作用蛋白激酶2 (receptor interacting protein kinase 2, RIPK2)是核苷酸结合寡聚化结构域蛋白1和2 (nucleotide-binding oligomerization domain containing protein 1/2, NOD1/2)下游的信号转导分子，在NOD介导的炎症反应中起到了关键的调控作用。NOD-RIPK2信号通路与多种炎症性疾病存在联系，本文对RIPK2的结构功能、RIPK2与炎症性疾病的关系以及RIPK2抑制剂的研发进展进行综述，希望为炎症性疾病的治疗提供新的思路。 Inflammation is a protective response that occurs in response to stimuli. However, dysregulated inflammation can lead to various inflammato-ry diseases. Receptor-interacting protein kinase 2 (RIPK2) is a downstream signaling molecule of nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) and plays a cru-cial role in regulating NOD-mediated inflammatory responses. The NOD-RIPK2 pathway is associ-ated with various inflammatory diseases. In this review, we summarize the recent advances in un-derstanding the role of RIPK2 in inflammatory diseases and the development of RIPK2 inhibitors, with the aim of providing new ideas for the treatment of inflammatory diseases.

 炎症性疾病，NOD，RIPK2，抑制剂, Inflammatory Diseases NOD RIPK2 Inhibitors 摘要

炎症是机体受到刺激后出现的一种保护性反应，然而，失调的炎症反应又会引发各种炎症性疾病。受体相互作用蛋白激酶2 (receptor interacting protein kinase 2, RIPK2)是核苷酸结合寡聚化结构域蛋白1和2 (nucleotide-binding oligomerization domain containing protein 1/2, NOD1/2)下游的信号转导分子，在NOD介导的炎症反应中起到了关键的调控作用。NOD-RIPK2信号通路与多种炎症性疾病存在联系，本文对RIPK2的结构功能、RIPK2与炎症性疾病的关系以及RIPK2抑制剂的研发进展进行综述，希望为炎症性疾病的治疗提供新的思路。

 关键词

炎症性疾病，NOD，RIPK2，抑制剂

 RIPK2: A New Therapeutic Target for Inflammatory Diseases<sup> </sup>

Yujun Lai, Heng Zheng*

College of Life Science and Technology, China Pharmaceutical University, Nanjing Jiangsu

Received: May 3rd, 2023; accepted: Jun. 9th, 2023; published: Jun. 21st, 2023

 ABSTRACT

Inflammation is a protective response that occurs in response to stimuli. However, dysregulated inflammation can lead to various inflammatory diseases. Receptor-interacting protein kinase 2 (RIPK2) is a downstream signaling molecule of nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) and plays a crucial role in regulating NOD-mediated inflammatory responses. The NOD-RIPK2 pathway is associated with various inflammatory diseases. In this review, we summarize the recent advances in understanding the role of RIPK2 in inflammatory diseases and the development of RIPK2 inhibitors, with the aim of providing new ideas for the treatment of inflammatory diseases.

Keywords:Inflammatory Diseases, NOD, RIPK2, Inhibitors

Copyright © 2023 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

炎症是机体在出现创伤或受到感染后出现的一种保护性的生理反应。该反应有助于损伤组织的修复以及抵御细菌、病毒等病原微生物。然而，过度的炎症反应会产生大量自由基、趋化因子和细胞因子，导致组织损伤，进一步引发各种炎症性疾病 [ 1 ] [ 2 ] 。

受体相互作用蛋白激酶(receptor interacting protein kinase, RIPK) 2是已知的7个RIPK家族成员之一，它是核苷酸结合寡聚化结构域蛋白(nucleotide-binding oligomerization domain containing protein, NOD) 1和2下游的信号转导分子，对NOD介导的炎症反应具有关键的调控作用 [ 3 ] 。近年来，研究发现，NOD-RIPK2信号通路在调控感染性炎症方面发挥了重要作用，并且NOD-RIPK2信号通路的失调与类风湿性关节炎、炎症性肠病等疾病的发生密切相关 [ 4 ] [ 5 ] 。

 2. RIPK2的结构和信号传导功能

RIPK2 (又被称为RIP2, RICK或CARDIAK)最早于1998年被三个不同的课题组先后发现和报道 [ 6 ] [ 7 ] [ 8 ] 。RIPK2全长为541aa，其N端含有RIPK家族高度保守的丝氨酸/苏氨酸激酶结构域(kinase domain, KD)，其C端带有半胱氨酸蛋白酶激活与募集结构域(caspase activation and recruitment domain, CARD)，两个结构域间存在一段中间结构域(intermediate domain, ID)。RIPK2在人体内的多种组织和细胞中表达，其中主要表达在心脏、胰腺、胎盘等组织中以及淋巴母细胞、肠上皮细胞等细胞中 [ 6 ] [ 8 ] 。

早期的功能研究发现，RIPK2可以调控细胞凋亡 [ 6 ] [ 7 ] 。目前，主流的观点认为，RIPK2主要参与调控NOD1和NOD2通路的信号转导以及它们下游的核因子κB (nuclear factor-kappa B, NF-Κb)和丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)通路的激活 [ 9 ] 。NOD1和NOD2是分布在胞质中的模式识别受体，其中NOD1可识别来自革兰氏阴性菌和部分革兰氏阳性菌的细胞壁肽聚糖的γ-d-谷氨酰基–内消旋–二氨基庚二酸(γ-d-glutamyl-meso-diaminopimelic acid, IE-DAP)，NOD2则可识别大多数细菌的细胞壁肽聚糖中的胞壁酰二肽(muramyl dipeptide, MDP) [ 10 ] [ 11 ] [ 12 ] 。NOD1与NOD2会在识别配体后将发生构象改变，并通过其N端的CARD结构域产生同型CARD-CARD相互作用来募集RIPK2。被募集的RIPK2会在cIAP1、cIAP2和XIAP等E3泛素连接酶的作用下发生K63泛素化，并通过K63泛素链结合泛素连接酶复合物LUBAC，随后发生M1泛素化 [ 13 ] [ 14 ] [ 15 ] 。随后，RIPK2通过K63和M1两种泛素链分别结合由转化生长因子β激活激酶1 (TGFβ activated kinase 1, TAK1)、TAK1结合蛋白(TAK1 Binding Protein, TAB) 1和TAB2或TAB3组成的TAK1-TAB复合物，以及由κB抑制因子激酶(inhibitor of kappa b kinase, IKK) α、IKKβ和nemo (即IKKγ)组成的IKK复合物，最终激活MAPK和NF-κb通路并调控一系列的炎症反应 [ 16 ] [ 17 ] 。

除此之外，还有研究表明，RIPK2在部分细胞中调控了I型干扰素的释放。在肠上皮细胞中，当NOD1识别配体并发生活化后，其可促进下游的RIPK2与TNF受体相关因子(TNFR-associated factor, TRAF) 3发生结合，随后激活TRAF3下游的TRAF家族成员关联NF-κB激活因子(TRAF family member associated NF-κB activator, TANK)结合激酶(TANK-Binding Kinase, TBK) 1和IKKε，从而促进IFN调节因子(IFN regulatory factor, IRF) 7的核移位激活以及I型干扰素的释放 [ 18 ] 。而在巨噬细胞中，当NOD2识别某些细菌特有的N-乙二醇化MDP后，RIPK2以及TBK1和IRF5等分子对细胞释放I型干扰素是不可或缺的 [ 19 ] 。

 3. RIPK2与感染性炎症

NOD1和NOD2是宿主防御的重要组成部分，在机体识别和清除病原微生物的过程中具有重要意义 [ 20 ] 。作为NOD1和NOD2下游的关键信号传导分子，RIPK2对细菌、真菌、衣原体和病毒等多种病原微生物感染引发的炎症反应具有重要调控作用。

3.1. 细菌感染

RIPK2调控了机体对单核增生李斯特菌(L. Monocytogenes)的应答。在被单核增生李斯特菌感染后，与野生型(wild type, WT)小鼠体内分离的骨髓来源的巨噬细胞BMDM相比，从RIPK2敲除(knockout, KO)小鼠体内分离的BMDM释放的炎症因子TNF-α和IL-6明显减少 [ 21 ] 。同时，与WT小鼠相比，RIPK2 KO小鼠对单核增生李斯特菌的敏感性明显增加，具体表现为RIPK2 KO小鼠在感染后出现更高的死亡率以及RIPK2 KO小鼠的肝脏、脾脏中具有更高的细菌负荷 [ 22 ] 。

RIPK2调控了机体在受到大肠杆菌(E. coli)感染后发生的炎症反应。在被大肠杆菌感染后，与WT小鼠体内分离的细胞相比，RIPK2 KO小鼠体内分离的BMDM和骨髓来源的树突状细胞BMDC释放的IL-6和IL-23明显减少。另一方面，小鼠在气管滴注大肠杆菌后会发生肺炎。与WT小鼠相比，RIPK2 KO小鼠的肺泡灌洗液中炎症因子、趋化因子的含量以及中性粒细胞的数量明显减少，且RIPK2 KO小鼠肺部大肠杆菌的细菌负荷更高。然而，由于肺部出现的炎症反应更轻，RIPK2 KO小鼠的肺部病理损伤明显轻于WT小鼠 [ 23 ] 。

RIPK2与机体的抗分歧杆菌感染有关。我国的两项独立的病例基因研究发现，具有RIPK2的单核苷酸多态性(single nucleotide polymorphism, SNP)的病人对结核分歧杆菌引发的结核病和麻风分歧杆菌(M. leprae)引发的麻风病表现出了更高的易感性 [ 24 ] [ 25 ] 。此外，有研究证明，与WT小鼠体内分离的BMDM相比，RIPK2KO小鼠体内分离的BMDM在受到结核分歧杆菌(M. tuberculosis)感染后分泌I型干扰素的能力明显减弱 [ 19 ] 。

 3.2. 真菌和衣原体感染

RIPK2参与了真菌和衣原体感染引起的应答。有研究发现，在受到烟曲霉(A. fumigatus)感染后，小鼠巨噬细胞Raw 264.7和人角膜内皮细胞HECEs中NOD2和RIPK2的表达水平明显增加，伴随着IL-8、TNF-α等炎症因子的释放。并且，当NOD2的表达被抑制后，烟曲霉感染不会导致细胞中RIPK2和NF-κB的表达上调，同时炎症因子的释放也明显减少，表明NOD2-RIPK2信号通路介导了烟曲霉感染引起的细胞的炎症因子分泌 [ 26 ] [ 27 ] 。

此外，研究发现，在受到衣原体(C. muridarum)感染后，小鼠脾脏中IL-6的表达水平明显增加。与WT小鼠相比，RIPK2 KO小鼠的脾脏中IL-6的表达水平更低，脾脏中的衣原体负荷更高，表明RIPK2在体内对衣原体的清除起到了促进作用 [ 28 ] 。

 3.3. 病毒感染

RIPK2在抗病毒反应中发挥了调控作用。人类巨细胞病毒(HCMV)感染会诱导人包皮成纤维细胞HFF的RIPK2的表达。与对照细胞相比，敲低(knockdown, KD) RIPK2表达的HFF在受到感染后的IFN-β、CXCL10等炎症因子的表达明显减少 [ 29 ] 。相反，对细胞进行RIPK2过表达后，HCMV在HFF和神经胶质瘤细胞U373中的复制均被明显抑制 [ 30 ] [ 31 ] 。

同时，RIPK2在不同病毒感染引发的炎症反应中的调控作用有所不同。在感染小鼠诺瓦克病毒-1 (MNV-1)后，与WT小鼠相比，RIPK2 KO小鼠因继发细菌感染出现的TNF-α的释放和死亡明显减少 [ 32 ] 。该现象表明，在抗MNV-1感染的过程中，RIPK2促进了体内炎症反应的发生。然而，在PR8甲型流感病毒感染中，与WT小鼠相比，RIPK2 KO小鼠肺部出现更多的IFN-γ和IL-18等细胞因子的释放，肺部损伤更严重，并且RIPK2 KO小鼠更容易发生死亡 [ 33 ] 。该结果说明，在PR8病毒感染的情况下，RIPK2对体内过度激活的炎症反应起到了限制的作用。

 4. RIPK2与类风湿性关节炎

类风湿性关节炎(rheumatoid arthritis, RA)是一种以对称性关节病变和关节滑膜炎为特征的慢性炎症疾病，其临床表现为关节疼痛、变形和功能丧失 [ 34 ] [ 35 ] 。据初步统计，在1990年到2010年间，全球RA患者的数量约保持在全球总人口的0.24%，预计该比例到2015年已上升至0.5%到1% [ 36 ] [ 37 ] 。RA会严重影响患者的生活质量，同时，RA导致的患者的运动和工作能力下降会给社会带来沉重的经济负担 [ 38 ] 。

临床对RA的诱因和发病机制的研究仍然处于探索阶段。目前，性别因素、遗传因素和环境因素被认为是影响RA发病的主要因素 [ 39 ] 。同时，破骨细胞和成骨细胞的失衡、巨噬细胞样滑膜细胞和成纤维细胞样滑膜细胞的过度增殖以及细胞因子引发的炎症等被认为是RA的成因 [ 40 ] [ 41 ] 。

此前，有研究报道了RIPK2与RA的关联。与骨关节炎(osteoarthritis, OA)患者的细胞相比，RA患者的外周血单核细胞PBMC和滑膜液T细胞SFTC中的NOD2与RIPK2的表达水平更高 [ 42 ] 。另一方面，给小鼠注射甲基化的牛血清白蛋白可建立关节炎动物模型。与WT小鼠相比，RIPK2 KO小鼠在造模后滑膜液中的中性粒细胞数量更少，且RIPK2 KO小鼠的痛觉阈值降低和软骨损伤的症状更轻。同时，RIPK2 KO小鼠的关节腔中TNF-α、IL-17和KC等炎症因子的含量水平更低 [ 43 ] ，表明缺失RIPK2对关节炎小鼠具有保护作用。这些现象提示RIPK2参与了RA的发生，并有可能成为RA的治疗靶点。

 5. RIPK2与炎症性肠病

炎症性肠病(inflammatory bowel disease, IBD)是一类慢性的、易复发的胃肠道炎症疾病，包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crohn’s disease, CD)两种类型。其中，UC仅在结肠发生，而CD可在胃肠道的任何部位发生，但通常发生在回肠 [ 44 ] 。近年来，IBD在全世界的发病率逐渐上升 [ 45 ] 。虽然目前我国的IBD发病率远低于欧美国家，但在近20年间，我国的IBD病例数也在迅速上升。据统计，在2005年至2014年间，我国的IBD病例数为35万例，预计此数字到2025年将会增加至150万 [ 46 ] 。考虑到IBD对患者生活质量造成的严重影响，以及对社会的经济和医疗带来的压力与负担，IBD已成为需要解决的重大社会健康问题 [ 47 ] 。

迄今为止，IBD的诱因和发病机制尚未完全明确。目前有许多观点认为，IBD的发病可能与遗传、环境、免疫、饮食和心理等多种因素有关。据报道，IBD有家族聚集性，IBD患者家属人群的IBD发病率高于普通人群 [ 48 ] 。而在IBD的患者和结肠炎模型的小鼠中观察到肠道微生物失调的现象，提示肠道微生物可能与IBD的发生有关 [ 49 ] 。免疫因素也被认为是影响IBD发病的重要因素之一。在肠道黏膜出现损伤后，分布在肠道的大量抗原将入侵肠组织，随后引发炎性细胞浸润，继而引发免疫反应。聚集的炎性细胞会释放大量的IL-6、IL-8、TNF-α等细胞因子，这些细胞因子调控了各种免疫细胞和非免疫细胞的相互作用，并可能与IBD的发生有关 [ 50 ] 。

近年来，越来越多的证据表明，NOD2-RIPK2通路介导的炎症反应影响了IBD的发生。遗传研究发现，NOD2的受体失活功能缺陷的基因突变会导致病人对克罗恩病的敏感性增加 [ 51 ] 。此外，虽然尚无研究表明RIPK2基因突变与IBD有关，但有研究发现，与不发病的对照组织相比，CD和UC患者的肠病变组织中RIPK2的蛋白水平明显升高 [ 52 ] [ 53 ] 。并且，在CD患者的肠病变组织中还可观察到RIPK2的磷酸化，表明RIPK2在CD患者的肠病变区域发生了激活 [ 53 ] 。除此之外，还有研究发现，与对照组织相比，IBD患者的发病区域的肠组织中对RIPK2的泛素化修饰具有重要作用的cIAP1、cIAP2等E3连接酶的表达水平也同样升高。同时，IBD患者的肠病变组织中RIPK2的表达与TNF-α和IL-6等炎症因子的表达成正相关 [ 54 ] 。另一方面，动物实验表明，在用葡聚糖硫酸钠(dextran sulfate, DSS)或三硝基苯磺酸(trinitrobenzenesulfonic acid, TNBS)诱导结肠炎后，与对照小鼠相比，注射了抑制RIPK2表达的siRNA的小鼠的肠道病理损伤明显减轻 [ 54 ] 。这些发现进一步证明了RIPK2在IBD中的作用，并提示RIPK2是治疗IBD的潜在靶点。

 6. RIPK2抑制剂的研发进展

由于RIPK2在NOD介导的炎症反应和多种炎症性疾病中发挥了重要的调控作用，因此它被认为是一种有潜力的药物靶点 [ 55 ] 。近年来，一些研究团队对RIPK2抑制剂进行了鉴定和开发，并对这些抑制剂在治疗部分炎症性疾病方面的疗效进行了评估。

6.1. SB 203580

SB 203580是一种吡啶基咪唑类化合物，早期被认为是一种具有抗炎作用的P38 MAPK抑制剂。后续的研究发现其对RIPK2也具有抑制作用。SB 203580可以抑制MDP诱导的NF-κB活化 [ 56 ] 。此外，SB 203580对DSS或TNBS诱导的小鼠结肠的损伤具有改善作用，并且可以抑制小鼠结肠组织中炎症细胞因子的转录 [ 57 ] 。

 6.2. 酪氨酸激酶抑制剂

酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)是一类药物，可阻断酪氨酸激酶催化其底物。部分TKI具有多种靶点 [ 58 ] 。之前的研究发现，吉非替尼(Gefitinib)、厄洛替尼(Erlotinib)、瑞格非尼(Regorafenib)、索拉非尼(Sorafenib)和普纳替尼(Ponatinib)对RIPK2具有抑制作用 [ 59 ] [ 60 ] ，其中普纳替尼对RIPK2的抑制作用最强 [ 60 ] 。普纳替尼可抑制MDP刺激后RIPK2的磷酸化、泛素化和后续NF-κB通路的激活，以及炎症因子基因的转录。此外，在人类原代单核细胞中，普纳替尼可抑制MDP诱导的TNF释放 [ 60 ] 。体内数据表明，吉非替尼可以减轻MDP诱导的腹膜炎以及SAMP1/YitFc小鼠的自发性回肠炎 [ 61 ] 。

 6.3. OD36

OD36是一种具有RIPK2抑制活性的大环化合物。与吉非替尼相比，OD36对RIPK2的抑制作用更强，并且不会影响表皮生长因子受体(epidermal growth factor receptor, EGFR)，但会抑制激活素受体样激酶(activin receptor-like kinase, ALK) 2。体外研究表明，OD36可以抑制MDP刺激后NF-κB和MAPK通路的活化以及炎症因子的转录。此外，体内实验证明，OD36可以减少MDP诱导的腹膜炎小鼠模型的腹腔中性粒细胞和淋巴细胞浸润，并且减少浸润细胞中细胞因子和趋化因子的转录。在治疗MDP诱导的腹膜炎方面，OD36的效果优于吉非替尼 [ 61 ] 。

 6.4. WEHI-345

WEHI-345是WEHI医学研究所研发的一种选择性RIPK2抑制剂，其在结合并抑制RIPK2的同时，对其他RIPK家族成员或蛋白激酶没有明显的影响。WEHI-345可以阻断RIPK2与IAP的结合，延迟MDP诱导的RIPK2泛素化和NF-κB和MAPK通路的激活，并且抑制MDP刺激或细菌感染引起的细胞炎症因子的转录和释放。此外，体内研究表明，口服WEHI-345可以缓解小鼠的腹膜炎以及实验性自身免疫性脑脊髓炎 [ 62 ] 。

 6.5. GSK583和GSK2983559

GSK583是GSK公司早期报道的一种激酶抑制剂。它具有良好的特异性，在测试的300种激酶中，它对RIPK2的抑制作用最强，对其他激酶的影响较小。虽然除RIPK2外，GSK583还可以与RIPK3发生结合，但对RIPK3的活性基本没有影响。GSK583可在人类原代单核细胞内抑制NOD-RIPK2信号通路介导的炎症因子释放，而且对TLR、TNFR等通路介导的炎症不产生影响。此外，GSK583还可缓解MDP诱导的小鼠腹膜炎，并抑制IBD患者发病区域肠组织的炎症因子释放。然而，后续研究发现，在可用的剂量范围内，GSK583对人类无效 [ 63 ] 。

GSK2983559是GSK公司在对GSK583进行优化后得到的一种前药，其在体内被切割后转化为活性形式。与GSK583相比，活性形式的GSK2983559的心脏安全性更好，并且对RIPK2的抑制作用更强，但其选择性有所降低。活性形式的GSK2983559还可在人类的原代单核细胞以及人类的全血中显著抑制MDP诱导的炎症因子释放。此外，活性形式的GSK2983559可减轻TNBS诱导的结肠损伤并抑制IBD患者发病组织的炎症因子释放。与此同时，人体PK/PD的预测结果显示，GSK2983559口服后对人类有效 [ 64 ] 。

 6.6. 10W

10W是四川大学华西医院研究团队开发的一种RIPK2抑制剂。它对激酶的抑制作用表现出了良好的特异性，在抑制RIPK2活性的同时，仅对少数其他蛋白激酶产生影响。与WEHI-345相比，10W的代谢稳定性和安全性更好，并且对RIPK2活性以及MDP诱导的细胞炎症因子的转录和释放的抑制作用更强。此外，10W能够改善DSS诱导的结肠炎小鼠的腹泻、体重下降，并减少结肠的缩短和损伤。同时，10W对DSS诱导的结肠炎的治疗效果优于WEHI-345 [ 65 ] 。

 7. 结语

RIPK2是NOD信号通路的关键调控蛋白，其在多种炎症性疾病治疗中的潜力得到了研究。但是，RIPK2如何影响这些疾病的发生还未完全明确，后续的研究应尝试进一步阐明RIPK2调控疾病的机制，以提供更详细的依据来制定炎症性疾病的治疗策略。此外，RIPK2的抑制剂的开发虽然取得了一定的成果，但是尚无一种RIPK2抑制剂可供临床使用。未来的工作仍需重视RIPK2抑制剂的研发，为炎症性疾病的治疗提供更多的药物选择。

 文章引用

赖宇俊,郑 珩. RIPK2：治疗炎症性疾病的新靶点 RIPK2: A New Therapeutic Target for Inflammatory Diseases[J]. 生物过程, 2023, 13(02): 105-114. https://doi.org/10.12677/BP.2023.132015

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