细胞焦亡在狼疮性肾炎中的作用及干预进展^*

The involvement of pyroptosis in lupus nephritis: mechanistic insights and intervention strategies

摘要

细胞焦亡是细胞受到病原微生物或机体危险因子刺激后, 经含半胱氨酸的天冬氨酸特异性蛋白水解酶介导并通过消皮素D切割细胞膜, 最终导致细胞膜破裂和炎症因子释放的细胞死亡模式。狼疮性肾炎(LN)是系统性红斑狼疮的一种严重并发症, 表现为免疫复合物在肾脏沉积, 导致炎症反应和细胞损伤。细胞焦亡参与LN的形成, 并可能加速LN及其他狼疮症状的发展, 抑制细胞焦亡的进程有望改善LN的预后。本文综述了细胞焦亡在LN发病机制中的作用以及相关的干预研究进展, 旨在为LN的临床诊疗提供新的视角。

Abstract

Pyroptosis is a form of cell death orchestratd by cysteinyl aspartate specific proteinase (Caspase) and carried out through the cleavage of the cell membrane by gasdermin D following stimulation by pathogenic microorganisms or endogenous danger signals, culminating in cell membrane rupture and the release of inflammatory mediators. Lupus nephritis (LN) is a serious consequence of systemic lupus erythematosus, characterized by the accumulation of immune complexes in the kidneys, resulting in inflammatory reactions and cellular injury. Pyroptosis contributes to the establishment of LN and may expedite the progression of LN and other lupus manifestations. Inhibiting pyroptosis is anticipated to enhance the prognosis of LN. This review examines the function of pyroptosis in the pathogenesis of LN and the advancements in associated intervention studies, intending to offer a novel perspective for the clinical diagnosis and treatment of LN.

关键词

细胞焦亡 / 狼疮性肾炎 / 炎症因子 / 含半胱氨酸的天冬氨酸特异性蛋白水解酶 / 消皮素D

Key words

Pyroptosis / Lupus nephritis / Inflammatory factors / Caspases / Gasdermin D

参考文献

[1] 孙凌云, 刘昱东 . 狼疮肾炎诊治新进展[J]. 中华临床免疫和变态反应杂志, 2022, 16(5): 545-547.

[2] Sun L Y, Liu Y D. Latest progress in the diagnosis and treatment of lupus nephritis[J]. Chin J Allergy Clin Immunol, 2022, 16(5): 545-547.

[3] 胡欣欣, 郭兆安 . 细胞焦亡在糖尿病肾病中的作用及干预进展[J]. 国际老年医学杂志, 2024, 45(5): 610-614.

[4] Hu X X, Guo Z A. Pyroptosis in diabetic nephropathy: role and therapeutic advances[J]. Int J Geriatr, 2024, 45(5): 610-614.

[5] Liu Y, Lei H, Zhang W, et al. Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance[J]. Cell Death Dis, 2023, 14(7): 472.

[6] Li D, Wu M . Pattern recognition receptors in health and diseases[J]. Signal Transduct Target Ther, 2021, 6(1): 291.

[7] Yao J, Sterling K, Wang Z, et al. The role of inflammasomes in human diseases and their potential as therapeutic targets[J]. Signal Transduct Target Ther, 2024, 9(1): 10.

[8] Zhen H, Hu Y, Liu X, et al. The protease caspase—1: activation pathways and functions[J]. Biochem Biophys Res Commun, 2024, 717: 149978.

[9] Dai Z, Liu W C, Chen X Y, et al. Gasdermin D—mediated pyroptosis: mechanisms, diseases, and inhibitors[J]. Front Immunol, 2023, 14: 1178662.

[10] Matikainen S, Nyman T A, Cypryk W . Function and regulation of noncanonical caspase—4/5/11 inflammasome[J]. J Immunol, 2020, 204(12): 3063-3069.

[11] Al Mamun A, Shao C, Geng P, et al. Pyroptosis in diabetic peripheral neuropathy and its therapeutic regulation[J]. J Inflamm Res, 2024, 17: 3839-3864.

[12] Huang T, Yin H, Ning W, et al. Expression of inflammasomes NLRP1, NLRP3 and AIM2 in different pathologic classification of lupus nephritis[J]. Clin Exp Rheumatol, 2020, 38(4): 680-690.

[13] Fu R, Guo C, Wang S, et al. Podocyte activation of NLRP3 inflammasomes contributes to the development of proteinuria in lupus nephritis[J]. Arthritis Rheumatol, 2017, 69(8): 1636-1646.

[14] Honarpisheh M, Desai J, Marschner J A, et al. Regulated necrosis—related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis[J]. Biosci Rep, 2016, 36(6): e00425.

[15] Zhao J, Wang J, Zhou M, et al. Curcumin attenuates murine lupus via inhibiting NLRP3 inflammasome[J]. Int Immunopharmacol, 2019, 69: 213-216.

[16] Lai Y, Zhuang L, Zhu J, et al. Novel approach to alleviate lupus nephritis: targeting the NLRP3 inflammasome in CD8 ⁺CD69 ⁺ CD103 ⁺ T _RM cells [J]. J Transl Med, 2024, 22(1): 1139.

[17] Kahlenberg J M, Yalavarthi S, Zhao W, et al. An essential role of caspase 1 in the induction of murine lupus and its associated vascular damage[J]. Arthritis Rheumatol, 2014, 66(1): 152-162.

[18] Oliveira C B, Lima C, Vajgel G, et al. The role of NLRP3 inflammasome in lupus nephritis[J]. Int J Mol Sci, 2021, 22(22): 12476.

[19] Hirooka Y, Nozaki Y . Interleukin—18 in inflammatory kidney disease[J]. Front Med (Lausanne), 2021, 8: 639103.

[20] Cao H, Liang J, Liu J, et al. Novel effects of combination therapy through inhibition of caspase—1/gasdermin D induced—pyroptosis in lupus nephritis[J]. Front Immunol, 2021, 12: 720877.

[21] Elias E E, Lyons B, Muruve D A . Gasdermins and pyroptosis in the kidney[J]. Nat Rev Nephrol, 2023, 19(5): 337-350.

[22] Zhuang L, Luo X, Wu S, et al. Disulfiram alleviates pristane—induced lupus via inhibiting GSDMD—mediated pyroptosis[J]. Cell Death Discov, 2022, 8(1): 379.

[23] Shen J, Li F, Han X, et al. Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis[J]. Cell Commun Signal, 2024, 22(1): 308.

[24] Li Z, Guo J, Bi L . Role of the NLRP3 inflammasome in autoimmune diseases[J]. Biomed Pharmacother, 2020, 130: 110542.

[25] Ihim S A, Abubakar S D, Zian Z, et al. Interleukin—18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment[J]. Front Immunol, 2022, 13: 919973.

[26] Ziehr B K, MacDonald J A . Regulation of NLRPs by reactive oxygen species: a story of crosstalk[J]. Biochim Biophys Acta Mol Cell Res, 2024, 1871(8): 119823.

[27] Zhang D, Xu J, Ren J, et al. Myeloid—derived suppressor cells induce podocyte injury through increasing reactive oxygen species in lupus nephritis[J]. Front Immunol, 2018, 9: 1443.

[28] Zhang X, Wang Z, Zheng Y, et al. Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)[J]. Int J Mol Med, 2023, 51(4): 35 [pii].

[29] Wu X, Yang J, Wu J, et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome in systemic lupus erythematosus[J]. Biomed Pharmacother, 2024, 172: 116261.

[30] Wu C Y, Hua K F, Yang S R, et al. Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1— and SIRT3—mediated autophagy induction[J]. J Cell Mol Med, 2020, 24(23): 13609-13622.

[31] Wu C Y, Hua K F, Chu C L, et al. Tris DBA ameliorates accelerated and severe lupus nephritis in mice by activating regulatory T cells and autophagy and inhibiting the NLRP3 inflammasome[J]. J Immunol, 2020, 204(6): 1448-1461.

[32] Khwaza V, Aderibigbe B A . Potential pharmacological properties of triterpene derivatives of ursolic acid[J]. Molecules, 2024, 29(16): 3884.

[33] Chen L, Li F, Ni J H, et al. Ursolic acid alleviates lupus nephritis by suppressing SUMO1—mediated stabilization of NLRP3[J]. Phytomedicine, 2024, 130: 155556.

[34] Chen W Y, Wang H W, Yao S, et al. The natural sources, extraction, and nephroprotective function of oleanolic acid and ursolic acid: a review[J]. Food Health, 2024, 3: 20-32.

[35] Ma Q, Xu M, Jing X, et al. Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL—33/ST2 axis[J]. Cell Death Dis, 2023, 14(3): 174.

[36] Yang J . Structure, function, and regulation of inflammatory caspases in inflammation and pyroptosis[M]. Cleveland:Case Western Reserve University, 2019: 66-70.

[37] Zhu J, Chen Y, Chen Y, et al. STAT3 inhibition ameliorates renal interstitial inflammation in MRL/lpr mice with diffuse proliferative lupus nephritis[J]. Ren Fail, 2024, 46(1): 2358187.

[38] Shi X, Wang Z, Tang R, et al. Podocyte injury and death: new insights into lupus nephritis pathogenesis and therapy[J]. Rheumatol Autoimmun, 2023, 3(4): 193-204.

[39] Yap D, Li P H, Tang C, et al. Long—term results of triple immunosuppression with tacrolimus added to mycophenolate and corticosteroids in the treatment of lupus nephritis[J]. Kidney Int Rep, 2022, 7(3): 516-525.

[40] Liu L, de Leeuw K, van Goor H, et al. The role of antioxidant transcription factor Nrf2 and its activating compounds in systemic lupus erythematosus[J]. Antioxidants (Basel), 2024, 13(10): 1224.

[41] Mokra D, Joskova M, Mokry J . Therapeutic effects of green tea polyphenol (—)—epigallocatechin—3—gallate (EGCG) in relation to molecular pathways controlling inflammation, oxidative stress, and apoptosis[J]. Int J Mol Sci, 2022, 24(1): 340.

[42] Wu D, Ai L, Sun Y, et al. Role of NLRP3 inflammasome in lupus nephritis and therapeutic targeting by phytochemicals[J]. Front Pharmacol, 2021, 12: 621300.

[43] Sharma S, Habib S, Sahu D, et al. Chemical properties and therapeutic potential of citral, a monoterpene isolated from lemongrass[J]. Med Chem, 2021, 17(1): 2-12.

[44] Li D, Shi G, Wang J, et al. Baicalein ameliorates pristane—induced lupus nephritis via activating Nrf2/HO—1 in myeloid—derived suppressor cells[J]. Arthritis Res Ther, 2019, 21(1): 105.

基金资助

^*山东省自然科学基金项目(202208310056)