Interleukin-33-mediated bone immunity

doi:10.12307/2023.490

Abstract

Abstract: BACKGROUND: Osteoimmunology is a hot spot in the research on the mechanism of bone metabolic diseases in recent years. Interleukin-33 is an important new cytokine in bone immunology. It plays an important role in the progression of various bone metabolic diseases such as rheumatoid arthritis and osteoporosis. Its conduction pathway may become a potential target for clinical treatment.
OBJECTIVE: To review the research progress of interleukin-33 in osteoimmunology effect during bone metabolism.
METHODS: The articles related to interleukin-33, bone metabolism, and osteoimmunology were searched in PubMed, Web of Science, WanFang, and CNKI databases from the establishment of the database to June 2022, and finally 67 articles were included and summarized.
RESULTS AND CONCLUSION: (1) Interleukin-33 mediated bone immunity has a regulatory effect on bone metabolism. (2) Regulation of bone metabolism by interleukin-33 can activate the osteoblast Wnt/β-catenin pathway by reducing the expression of sclerostin. This pathway increases bone mass through a variety of mechanisms, including stem cell renewal, stimulation of pre-osteoblast replication, induction of osteoblastogenesis, inhibition of osteoblast and osteocyte apoptosis. Interleukin-33 can inhibit the expression of nuclear factor of activated T cells c1 and osteoclast formation by stimulating the expression of anti-osteoclast genes such as Irf-8, MafB, and Bcl6. Moreover, the expression levels of apoptosis molecules can be induced, resulting in osteoclast apoptosis. (3) Interleukin-33 can inhibit the expression of RANKL in type 2 innate lymphocytes and induce the production of interleukin-13, interleukin-4, and granulocyte-macrophage colony stimulating factor, thereby inhibiting the differentiation of osteoclasts. Interleukin-33 can induce the recruitment of regulatory T cells to inflammatory sites and inhibit Th1 cells, CD8+ T cells, and M1 macrophages to support the differentiation of osteogenic precursor cells and inhibit the expression of osteoclast costimulatory molecules, thereby suppressing osteoclast differentiation and function. Interleukin-33 also can activate naïve T cells to differentiate into a Th2 cells and produce Th2 cytokines, which can induce local recruitment of osteoclasts, resulting in increased local bone resorption and cartilage degeneration. (4) Interleukin-33 also can induce endothelial cell proliferation, migration, and morphological differentiation, promote angiogenesis, and have a certain protective effect against ischemic diseases. Regulatory effects of interleukin-33 on bone metabolism are bidirectional, the causes of bone metabolism disorders are diverse, and the microenvironment in different parts of the body is different. Therefore, controlling the regulatory effect of interleukin-33 is a new direction for the treatment of bone metabolism-related diseases.

Key words: interleukin-33, osteoimmunology, osteoblast, osteoclast, lymphocyte, endothelial cell

CLC Number:

Shen Mengran, Ren Yansong, Zhou Yu, Yue Debo, Ma Jinhui, Wang Bailiang. Interleukin-33-mediated bone immunity[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(29): 4723-4728.

Figures/Tables 4

2.2 IL-33概述 IL-33是IL-1家族的最新成员，与IL-1家族的IL-1β和IL-18基因序列和结构相似，其基因位于9号染色体(9p24.1)上，编码分子质量为30 kD的蛋白。IL-33受体(ST2)，由Il1rl1 基因编码，是Toll-like/IL-1受体(TLR/IL-1R)超家族成员[20]。 ST2基因位于2号染色体(2q12)上，主要有2种形式：SsT2和ST2L。跨膜ST2异构体(ST2L)是一种膜结合型异构体，可溶性ST2亚型(Sst2)缺少跨膜区和胞内区，是一种诱骗性受体，可向细胞外分泌，可中和IL-33生物学效应。ST2L和Sst2两者都是由Il1rl1 基因在2个不同启动子的控制下交替剪接而产生的[21-22]。 2.2.1 IL-33的来源研究已发现免疫细胞和组织实质细胞，如内皮细胞、树突状细胞、淋巴细胞和心肌细胞等细胞表达IL-33。最近研究发现，在成骨细胞、破骨细胞亦存在IL-33的表达。在没有促炎因子刺激的情况下，IL-33局限于细胞核中，然而当在应激和炎症等因素引起的组织损伤时，通过钾通道和钙依赖激活caspase-1后，IL-33前体被裂解，分泌型溶酶体膜与细胞膜融合，IL-33作为活性细胞因子被释放到细胞外。 2.2.2 IL-33的生物学功能 IL-33生物学效应广泛，可在细胞核内调节基因转录，也可通过转运至细胞外结合其他细胞的ST2受体，发挥生物学效应[23]。IL-33能够调节免疫细胞，可促进Treg向炎症处聚集，增强Treg的功能和对炎症环境的适应性[24]。IL-33也可诱导幼稚T细胞向Th2表型分化，促使Th2型细胞因子和趋化因子的释放介导Th2型免疫反应，并且可以改变巨噬细胞极化，产生抗炎递质减轻炎症反应[25]。此外，IL-33可促进嗜酸性粒细胞、嗜碱性粒细胞释放可增强细胞的黏附和趋化作用的炎症递质[26]。正是因为IL-33对免疫系统具有广泛调节作用，所以IL-33具有抗感染、抗肿瘤的效应。在抗感染方面，IL-33可维持CXCR2的表达，通过阻止TLR信号通路介导的G蛋白偶联受体激酶2(GRK2)的诱导，从而使中性粒细胞能够迁移到感染部位进行细菌清除[27]，并且可通过调节淋巴细胞的分化、聚集和诱导干扰素的产生，从而起到一定的抗病毒作用[28]。在抗肿瘤方面，IL-33通过调节免疫系统来调节肿瘤的微环境来干扰肿瘤的发生与转移。IL-33可激活2型天然淋巴细胞(ILC2)释放炎症因子，使肿瘤微环境发生改变，进而促使细胞毒性T细胞、树突状细胞募集进而杀伤肿瘤细胞[29-30]，并且可提高CD8+T细胞和NK细胞的增殖、活化和浸润和对肿瘤的识别能力，诱导干扰素γ、肿瘤坏死因子α等抗肿瘤细胞因子的释放，干扰肿瘤的增殖和转移[31]。 2.3 IL-33在骨骼系统中的作用 IL-33可通过影响成骨细胞、破骨细胞的前体细胞分化及细胞凋亡来调节骨重建，并且可通过诱导淋巴细胞的分化、聚集参与炎症局部骨代谢。此外，骨形成需要与血管形成协同，IL-33可诱导内皮细胞增殖、迁移和形态分化，促进血管形成，对骨形成和修复起到一定作用[32-33]。此外，IL-33以位点和性别依赖性方式对骨起保护作用[34]，同时体内IL-33及受体ST2水平受体内调节钙水平物质影响，如维生素D和甲状旁腺素，对骨代谢起到一定作用[35-36]。 2.3.1 IL-33对成骨细胞的作用成骨细胞由间充质干细胞分化而来。IL-33及其受体在骨细胞、成骨细胞、破骨细胞表达，尤其是成骨细胞中表达。SALEH等[35]提取小鼠颅骨中成骨细胞体外培养，用抗坏血酸、甘油磷酸钠和地塞米松诱导成骨细胞形成矿化结节，在加入IL-33诱导时发现矿化沉积增加一倍，硬化蛋白表达下降，表明IL-33可促进成骨细胞成熟和基质矿物质沉积；并且可作为成骨细胞旁分泌因子从而降低硬化蛋白的表达。硬化蛋白与成骨细胞膜上的低密度脂蛋白受体相关蛋白受体5/6(LRP5/6)上结合，进而抑制成骨细胞Wnt/β-catenin 通路，而Wnts可通过抑制间充质分化途径，促进成骨细胞分化、增殖和矿化活性，同时阻断成骨细胞凋亡[37]，也有研究发现IL-33可促进成骨细胞聚集，促进成骨[38]。但是目前IL-33对成骨细胞作用存在争议，SCHULZE等[39]也提取成骨细胞体外培养，用IL-33诱导成骨细胞矿化并测量与矿化相关基因表达量变化，实验结果却发现IL-33对基质矿化及矿化相关基因表达没有影响。 2.3.2 IL-33对破骨细胞的作用多核破骨细胞是巨噬细胞和单核细胞的分化产物，对骨骼发育、重构都有着关键的意义。破骨前体细胞主要在巨噬细胞集落刺激因子(M-CSF)和RANKL这两种细胞因子的作用下分化为破骨细胞[40]。RANKL与其受体RANK结合激活破骨细胞形成的主要调控因子——活性T细胞核因子c1(nuclear factor of activated T Cell C1，NFATC1)，从而诱导破骨细胞基因表达。骨保护素是RANKL的可溶性诱骗受体，是RANKL的抑制因子，RANKL和骨保护素之间的动态平衡调控者破骨细胞的数量[41]。IL-33抑制RANKL诱导的B淋巴细胞诱导成熟蛋白-1(B lymphocyte induced maturation protein-1，Blimp-1)的表达，Blimp-1可抑制干扰素调节因子8(interferon regulatory factor 8，Irf-8)、肌腱膜纤维肉瘤癌基因(musculoaponeurotic fibrosarcoma oncogene homolog B，MafB)、B淋巴细胞瘤-6基因(B-cell lymphoma/leukemia gene6，Bcl-6)等抗破骨细胞基因的表达，进而抑制NFATc1的表达，抑制破骨细胞的形成[42-43]。ZAISS等[44]利用过量表达肿瘤坏死因子的转基因小鼠建立自发性骨关节炎及软骨破坏模型进行体内实验，并从人体股骨骨髓中提取破骨细胞前体细胞进行体外实验，将实验组予以IL-33及ST2L激动剂进行处理；发现IL-33及ST2L激动剂处理后的转基因小鼠骨侵蚀及软骨破坏显著改善，并且对转基因小鼠骨骼进行Q-PCR分析，发现破骨细胞标志——抗酒石酸酸性磷酸酶(TRAP)和NFATC1基因表达显著减少；此外，IL-33直接作用于破骨前体细胞，通过粒细胞-巨噬细胞集落刺激因子 (granulocyte-macrophage colony stimulating factor，GM-CSF)以自分泌的方式将其分化为巨噬细胞，进而抑制破骨细胞形成。IL-33可诱导破骨细胞凋亡，LIMA等[38]发现ST2表达缺陷的小鼠与野生型小鼠相比，牙槽骨中成骨细胞减少，破骨细胞增多；因此又分离破骨细胞体外培养并用外源性IL-33进行处理，发现在RANKL存在情况下，IL-33可抑制破骨细胞分化和活性；并对细胞凋亡标志物进行检测，发现IL-33可使骨髓来源的破骨细胞细胞凋亡正调节因子表达显著增加，包括半胱天冬酶 (CASP) 1、3、7 和 8，使细胞凋亡负调节因子BCL2和NFKB1表达降低；IL-33使破骨细胞Ⅰ型促凋亡因子(FAS、FASL、肿瘤坏死因子相关凋亡诱导配体、肿瘤坏死因子α)和Ⅱ型促凋亡因子(FAS和BID)途径表达增加。目前IL-33对破骨细胞的作用存在争议，有学者实验发现IL-33和RANKL具有协同作用，共同刺激破骨细胞生成。IL-33可通过依赖ERK和p38 MAPK信号通路提高破骨细胞内RANKL mRNA的表达，并且降低骨保护素 mRNA的表达，进而促进功能性破骨细胞的形成[45-46]。另有研究资料表明IL-33还能升高BCl-2/Bax比率、抑制Caspase-3蛋白的活化，从而抑制破骨细胞凋亡。 2.3.3 IL-33对骨骼系统中其他细胞的作用 IL-33对骨细胞的作用：骨细胞起源于成骨细胞，骨细胞表达IL-33 mRNA。IL-33可促进成骨细胞分化成熟，间接促进骨细胞的生成。IL-33对骨细胞的作用可能是通过调节成骨细胞和破骨细胞之间的平衡来间接调节，但有研究认为IL-33对正常骨重构不产生直接作用[47]。 IL-33对骨髓间充质干细胞的作用：骨髓间充质干细胞是一种具有分化形成骨、软骨、脂肪、神经及成肌细胞的多种分化潜能的细胞亚群。IL-33对骨髓间充质干细胞具有保护性作用。IL-33与骨髓间充质干细胞体外共培养研究发现，IL-33高表达可以减少骨髓间充质干细胞的早期凋亡，但是不影响其活力[48]，此外也有研发现IL-33可通过调节白细胞介素6和转化生长因子β的分泌来影响骨髓间充质干细胞的生物学效应[49]。IL-33对骨髓间充质干细胞的影响有利于对局部损伤组织进行修复。 IL-33对软骨细胞的作用：软骨细胞来源于成软骨细胞，其主要功能是合成和分泌蛋白多糖、Ⅱ型胶原等细胞外基质。IL-33对软骨细胞的功能会产生一定的影响。研究发现，骨关节炎患者软骨细胞中IL-33水平升高，尤其是承重部位的软骨细胞。IL-33可诱导基质金属蛋白酶的产生，抑制Ⅱ型胶原的表达，进而促进软骨细胞退化[50]。 IL-33对骨组织作用见表1。"

2.3.4 IL-33介导淋巴细胞调节骨代谢 2型天然淋巴细胞(Innate lymphoid cells 2，ILC2s)是一种组织驻留细胞，在不同的器官中通过感知周围环境因素发挥不同的作用。有研究发现骨髓中稳定状态的ILC2s比T细胞或成骨细胞表达更高水平的RANKL。IL-33可促使 ILC2s下调RANKL的表达，并且诱导ILC2s产生白细胞介素13、白细胞介素4和GM-CSF来抑制破骨细胞的分化。此外，研究表明ILC2在IL-33依赖的炎症中通过产生2型细胞因子来防止过度的骨破坏[51]。调节性T细胞(Tregs)是调控体内自身免疫反应性的T细胞亚群。调节性T细胞在骨的修复和再生中起着重要作用。调节性T细胞可通过释放多种细胞因子的方式调控骨免疫微环境、维持骨微环境稳态促进骨组织再生。调节性T细胞可以组成性表达高亲和性的白细胞介素2 受体CD25和转录因子叉头蛋白3(forkhead box protein 3，Foxp3)，它通过细胞毒T淋巴细胞相关抗原(CTLA)-4与破骨细胞前体中的B7-1和B7-2结合，抑制破骨细胞形成，进而抑制骨质破坏。同时调节性T细胞还可产生白细胞介素4、白细胞介素10、转化生长因子β等细胞因子，这些细胞因子兼有抗炎及抑制破骨细胞的作用[52]。调节性T细胞可使破骨细胞表面共刺激分子表达下降，导致破骨细胞的分化和功能受到抑制，并且调节性T细胞可通过CTLA-4-CD80/86轴降低外周破骨细胞前体细胞的数量和存活力以及单核细胞的破骨细胞分化潜能[17，53]。除此之外，Foxp3+调节性T细胞还具有调控脂肪组织的代谢功能、肌肉细胞的再生、淋巴造血功能、成骨细胞的发育和功能。体外CD4+CD25+调节性T细胞与破骨细胞共培养实验发现CD4+CD25+调节性T细胞通过增加白细胞介素10和转化生长因子β化分泌，在体外抑制破骨细胞分化和骨吸收[54-55]。体内实验也表明调节性T细胞能够保护肿瘤坏死因子α诱导的骨破坏和卵巢切除诱导的骨丢失[56]。IL-33能够促进转化生长因子β1介导的调节性T细胞分化，它又为调节性T细胞在炎症组织中的积累与维持，提供了必要的信号。有研究表明，IL-33/ST2信号可使CD4+Foxp3-T细胞转化为表达Foxp3+的调节性T细胞，而外源性IL-33能够上调Foxp3+调节性T细胞数量[57-58]。此外，IL-33对于调节性T细胞的生成和其抑制功能的维持必不可少[59]。辅助性T细胞(Th)是一种激活后可以分泌细胞因子，进而调节免疫反应的T细胞。IL-33激活幼稚T细胞，促进其向Th2型表型成熟，释放Th2型细胞因子和趋化因子，其中包括白细胞介素31[60-61]。白细胞介素31诱导趋化因子、金属蛋白酶和促炎细胞因子的产生，诱导局部炎症部位的破骨细胞募集、分化，造成局部骨吸收增加，软骨细胞退化[62-63]。 2.3.5 IL-33介导巨噬细胞调节骨代谢巨噬细胞是骨免疫反应中起重要作用的调节细胞，可释放多种调节因子调控骨免疫环境，维持骨微环境稳态促进骨组织再生。巨噬细胞主要来源于髓系单核细胞，在早在胚胎发育过程也产生的一些组织驻留的巨噬细胞，共同参与组织修复、免疫监视和体内稳态的维持[64]。在不同的疾病，疾病的各个时期以及内环境改变的情况下，巨噬细胞可以特定分化为不同类型的细胞，主要包括促进炎症型以及抑制炎症型。巨噬细胞可分为M1型和M2型，而M2型又被分为M2a、M2b和M2c三种亚群。其中M1型巨噬细胞主要在炎症早期起作用，通过分泌炎性细胞因子肿瘤坏死因子α、白细胞介素1β及趋化因子(如CC趋化因子配体2)，促进炎症反应；而M2型巨噬细胞则主要分泌抗炎因子(如白细胞介素10)、转化生长因子β、血小板源性生长因子等发挥抗炎作用，并通过调节细胞外基质沉积、血管生成等参与组织修复过程。M1型巨噬细胞可通过分泌肿瘤坏死因子α、白细胞介素1、白细胞介素6等细胞因子，调控骨免疫微环境，促进破骨细胞分化，导致破骨吸收；M2巨噬细胞可诱导间充质干细胞成骨分化，吞噬凋亡间充质干细胞以及分泌促再生细胞因子等方式调节骨组织再生，促进骨修复。IL-33通过将Th17/Th1反应转变为Th2反应，以及诱导巨噬细胞向抗炎性M2型极化，也可通过TLR-4信号通路诱导自噬，并且可激活AMPK诱导产生活性氧，进而影响有丝分裂，促进巨噬细胞向M2极化，进而改善骨免疫环境，促进骨组织再生修复[65]。淋巴细胞及巨噬细胞对骨代谢影响见表2。"

References

[1] RAI V, DILISIO MF, SAMADI F, et al. Counteractive Effects of IL-33 and IL-37 on Inflammation in Osteoarthritis. Int J Environ Res Public Health. 2022;19(9):5690.
[2] 冯瑶,吴素琴,吴英良.IL-33对RANKL诱导破骨细胞增殖和凋亡的影响[J].沈阳药科大学学报,2021,38(9):935-941.
[3] KELSEN SG, AGACHE IO, SOONG W, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial. J Allergy Clin Immunol. 2021;148(3):790-798.
[4] GINALDI L, DE MARTINIS M. Osteoimmunology and Beyond. Curr Med Chem. 2016;23(33):3754-3774.
[5] SIMONET WS, LACEY DL, DUNSTAN CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309-319.
[6] ANDERSON DM, MARASKOVSKY E, BILLINGSLEY WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390(6656):175-179.
[7] YASUDA H, SHIMA N, NAKAGAWA N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95(7):3597-3602.
[8] LACEY DL, TIMMS E, TAN HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93(2):165-176.
[9] TAKAHASHI N, UDAGAWA N, SUDA T. A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function. Biochem Biophys Res Commun. 1999;256(3): 449-455.
[10] ARRON JR, CHOI Y. Bone versus immune system. Nature. 2000;408(6812):535-536.
[11] THEILL LE, BOYLE WJ, PENNINGER JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol. 2002;20:795-823.
[12] TAKAYANAGI H, KIM S, KOGA T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889-901.
[13] MARTIN TJ, SIMS NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med. 2005;11(2):76-81.
[14] TAKAYANAGI H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7(4):292-304.
[15] GRASSI F, MANFERDINI C, CATTINI L, et al. T cell suppression by osteoclasts in vitro. J Cell Physiol. 2011;226(4):982-990.
[16] KONG N, LAN Q, SU W, et al. Induced T regulatory cells suppress osteoclastogenesis and bone erosion in collagen-induced arthritis better than natural T regulatory cells. Ann Rheum Dis. 2012;71(9):1567-1572.
[17] BOZEC A, ZAISS M, KAGWIRIA R, et al. T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Sci Transl Med. 2014;6(235):235r-260r.
[18] MIYAZAKI Y, NAKAYAMADA S, KUBO S, et al. Th22 Cells Promote Osteoclast Differentiation via Production of IL-22 in Rheumatoid Arthritis. Front Immunol. 2018;9:2901.
[19] OMATA Y, FRECH M, LUCAS S, et al. Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss. Bone. 2020;136:115335.
[20] MARTYNOVA E, RIZVANOV A, URBANOWICZ RA, et al. Inflammasome Contribution to the Activation of Th1, Th2, and Th17 Immune Responses. Front Microbiol. 2022;13:851835.
[21] PINTO SM, SUBBANNAYYA Y, REX D, et al. A network map of IL-33 signaling pathway. J Cell Commun Signal. 2018;12(3):615-624.
[22] BARICHELLO T. The role of innate lymphoid cells (ILCs) in mental health. Discov Ment Health. 2022;2(1):2.
[23] LI Z, JIANG W, CHU H, et al. Exploration of potential mechanism of interleukin-33 up-regulation caused by 1,4-naphthoquinone black carbon in RAW264.7 cells. Sci Total Environ. 2022;835:155357.
[24] SCHIERING C, KRAUSGRUBER T, CHOMKA A, et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014;513(7519):564-568.
[25] PI L, FANG B, MENG X, et al. LncRNA XIST accelerates burn wound healing by promoting M2 macrophage polarization through targeting IL-33 via miR-19b. Cell Death Discov. 2022;8(1):220.
[26] MIYATA J, YOKOKURA Y, MORO K, et al. 12/15-Lipoxygenase Regulates IL-33-Induced Eosinophilic Airway Inflammation in Mice. Front Immunol. 2021;12: 687192.
[27] ROZARIO C, MARTINEZ-SOBRIDO L, MCSORLEY HJ, et al. Could Interleukin-33 (IL-33) Govern the Outcome of an Equine Influenza Virus Infection? Learning from Other Species. Viruses. 2021;13(12):2519.
[28] MURDACA G, PALADIN F, TONACCI A, et al. Involvement of Il-33 in the Pathogenesis and Prognosis of Major Respiratory Viral Infections: Future Perspectives for Personalized Therapy. Biomedicines. 2022;10(3):715.
[29] SARANCHOVA I, HAN J, ZAMAN R, et al. Type 2 Innate Lymphocytes Actuate Immunity Against Tumours and Limit Cancer Metastasis. Sci Rep. 2018;8(1):2924.
[30] EBERL G, COLONNA M, DI SANTO JP, et al. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science. 2015;348(6237):a6566.
[31] YANG K, TIAN C, ZHANG C, et al. The Controversial Role of IL-33 in Lung Cancer. Front Immunol. 2022;13:897356.
[32] KENSWIL K, JARAMILLO AC, PING Z, et al. Characterization of Endothelial Cells Associated with Hematopoietic Niche Formation in Humans Identifies IL-33 As an Anabolic Factor. Cell Rep. 2018;22(3):666-678.
[33] TUCKERMANN J, ADAMS RH. The endothelium-bone axis in development, homeostasis and bone and joint disease. Nat Rev Rheumatol. 2021;17(10):608-620.
[34] LOUISY A, GEOFFROY V, HALGAND B, et al. Interleukin-33 Deficiency Exacerbates Bone Loss Associated with Porphyromonas Gingivalis-Induced Experimental Periodontitis in Female Mice. Cell Physiol Biochem. 2022;56(3):270-281.
[35] SALEH H, EELES D, HODGE JM, et al. Interleukin-33, a target of parathyroid hormone and oncostatin m, increases osteoblastic matrix mineral deposition and inhibits osteoclast formation in vitro. Endocrinology. 2011;152(5):1911-1922.
[36] WIERZBICKA JM, PIOTROWSKA A, PURZYCKA-BOHDAN D, et al. The Effects of Vitamin D on the Expression of IL-33 and Its Receptor ST2 in Skin Cells; Potential Implication for Psoriasis. Int J Mol Sci. 2021;22(23):12907.
[37] LOJK J, MARC J. Roles of Non-Canonical Wnt Signalling Pathways in Bone Biology. Int J Mol Sci. 2021;22(19):10840.
[38] LIMA IL, MACARI S, MADEIRA MF, et al. Osteoprotective Effects of IL-33/ST2 Link to Osteoclast Apoptosis. Am J Pathol. 2015;185(12):3338-3348.
[39] SCHULZE J, BICKERT T, BEIL FT, et al. Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells. J Bone Miner Res. 2011;26(4):704-717.
[40] MCDONALD MM, KIM AS, MULHOLLAND BS, et al. New Insights Into Osteoclast Biology. JBMR Plus. 2021;5(9):e10539.
[41] Ono T, Nakashima T. Recent advances in osteoclast biology. Histochem Cell Biol. 2018;149(4):325-341.
[42] DE MARTINIS M, GINALDI L, SIRUFO MM, et al. Alarmins in Osteoporosis, RAGE, IL-1, and IL-33 Pathways: A Literature Review. Medicina (Kaunas). 2020;56(3):138.
[43] KIYOMIYA H, ARIYOSHI W, OKINAGA T, et al. IL-33 inhibits RANKL-induced osteoclast formation through the regulation of Blimp-1 and IRF-8 expression. Biochem Biophys Res Commun. 2015;460(2):320-326.
[44] ZAISS M, KUROWSKA-STOLARSKA M, BOHM C, et al. IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-alpha-mediated bone loss. J Immunol. 2011;186(11):6097-6105.
[45] MUN SH, KO NY, KIM HS, et al. Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytes. Cell Mol Life Sci. 2010;67(22): 3883-3892.
[46] MINE Y, MAKIHIRA S, YAMAGUCHI Y, et al. Involvement of ERK and p38 MAPK pathways on Interleukin-33-induced RANKL expression in osteoblastic cells. Cell Biol Int. 2014;38(5):655-662.
[47] SAIDI S, BOURI F, LENCEL P, et al. IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling. Cytokine. 2011;53(3):347-354.
[48] 左建峰. IL-33修饰的BMSCs对心肌梗死炎症和心功能的影响分析[D].苏州:苏州大学胸心血管外科学,2017.
[49] TERRAZA C, FUENTES R, PINO-LAGOS K. IFN-gamma and IL-33 modulate mesenchymal stem cells function targeting Th1/Th17 axis in a murine skin transplantation model. Cytokine. 2018;111:317-324.
[50] LI C, CHEN K, KANG H, et al. Double-stranded RNA released from damaged articular chondrocytes promotes cartilage degeneration via Toll-like receptor 3-interleukin-33 pathway. Cell Death Dis. 2017;8(11):e3165.
[51] MOMIUCHI Y, MOTOMURA Y, SUGA E, et al. Group 2 innate lymphoid cells in bone marrow regulate osteoclastogenesis in a reciprocal manner via RANKL, GM-CSF and IL-13. Int Immunol. 2021;33(11):573-585.
[52] DOHNKE S, MOEHSER S, SURNOV A, et al. Role of Dynamic Actin Cytoskeleton Remodeling in Foxp3(+) Regulatory T Cell Development and Function: Implications for Osteoclastogenesis. Front Immunol. 2022;13:836646.
[53] FISCHER L, HERKNER C, KITTE R, et al. Foxp3(+) Regulatory T Cells in Bone and Hematopoietic Homeostasis. Front Endocrinol (Lausanne). 2019;10:578.
[54] XU H, ZHAO H, LU C, et al. Triptolide Inhibits Osteoclast Differentiation and Bone Resorption In Vitro via Enhancing the Production of IL-10 and TGF-beta1 by Regulatory T Cells. Mediators Inflamm. 2016;2016:8048170.
[55] XIA Y, FAN D, LI X, et al. Yi Shen Juan Bi Pill Regulates the Bone Immune Microenvironment via the JAK2/STAT3 Signaling Pathway in Vitro. Front Pharmacol. 2021;12:746786.
[56] ZAISS M, FREY B, HESS A, et al. Regulatory T cells protect from local and systemic bone destruction in arthritis. J Immunol. 2010;184(12):7238-7246.
[57] GAJARDO T, MORALES RA, CAMPOS-MORA M, et al. Exogenous interleukin-33 targets myeloid-derived suppressor cells and generates periphery-induced Foxp3(+) regulatory T cells in skin-transplanted mice. Immunology. 2015;146(1): 81-88.
[58] KAWAI K, UCHIYAMA M, HESTER J, et al. IL-33 drives the production of mouse regulatory T cells with enhanced in vivo suppressive activity in skin transplantation. Am J Transplant. 2021;21(3):978-992.
[59] SIEDE J, FROHLICH A, DATSI A, et al. IL-33 Receptor-Expressing Regulatory T Cells Are Highly Activated, Th2 Biased and Suppress CD4 T Cell Proliferation through IL-10 and TGFbeta Release. PLoS One. 2016;11(8):e161507.
[60] VOCCA L, DI SANO C, UASUF CG, et al. IL-33/ST2 axis controls Th2/IL-31 and Th17 immune response in allergic airway diseases. Immunobiology. 2015;220(8):954-963.
[61] MURDACA G, GRECO M, TONACCI A, et al. IL-33/IL-31 Axis in Immune-Mediated and Allergic Diseases. Int J Mol Sci. 2019;20(23):5856.
[62] DE MARTINIS M, SIRUFO MM, SUPPA M, et al. IL-33/IL-31 Axis in Osteoporosis. Int J Mol Sci. 2020;21(4):1239.
[63] LI C, CHEN K, KANG H, et al. Double-stranded RNA released from damaged articular chondrocytes promotes cartilage degeneration via Toll-like receptor 3-interleukin-33 pathway. Cell Death Dis. 2017;8(11):e3165.
[64] ALVAREZ MM, LIU JC, TRUJILLO-DE SG, et al. Delivery strategies to control inflammatory response: Modulating M1-M2 polarization in tissue engineering applications. J Control Release. 2016;240:349-363.
[65] LIN YC, LIN YC, TSAI ML, et al. IL-33 regulates M1/M2 chemokine expression via mitochondrial redox-related mitophagy in human monocytes. Chem Biol Interact. 2022;359:109915.
[66] CHOI YS, CHOI HJ, MIN JK, et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood. 2009;114(14):3117-3126.
[67] DONG Q, TIAN J, ZHENG W, et al. Interleukin-33 protects mice against hindlimb ischemic injury by enhancing endothelial angiogenesis. Int Immunopharmacol. 2022;109:108850.