PPAR-γ在巨噬细胞炎症调控中的作用及机制的研究进展

doi:10.3969/j.issn.1004-616x.2022.02.016

摘要/Abstract

摘要： 巨噬细胞是机体内主要的炎症效应细胞，一般可分化为促炎(M1)型和抗炎(M2)型两大类，针对巨噬细胞极化调控成为炎症相关疾病治疗的新靶点。研究表明，过氧化物酶体增殖物激活受体-γ(PPAR-γ)作为一个配体激活的核转录因子，可抑制M1型巨噬细胞促炎信号通路的启动，并促进M2型巨噬细胞抗炎信号的表达。本文主要综述了PPAR-γ在巨噬细胞抗炎症反应中的关键作用，以及PPAR-γ激动剂在脓毒症、肠道炎症、代谢性炎症和自身免疫性炎症疾病治疗中的应用，以期为相关基础研究和临床用药提供指导。

关键词: PPAR-γ, 巨噬细胞, 促炎反应, 抗炎反应, 氧化还原, 炎症调控

中图分类号:

364.5

涂永梅, 彭洁, 龙子, 孔德钦, 陈宇豪, 覃梓瀚, 刘瑞, 李文丽, 于卫华. PPAR-γ在巨噬细胞炎症调控中的作用及机制的研究进展[J]. 癌变·畸变·突变, 2022, 34(2): 158-161.

参考文献

[1] FAGHFOURI A H, KHAJEBISHAK Y, PAYAHOO L, et al. PPAR-gamma agonists: potential modulators of autophagy in obesity[J]. Eur J Pharmacol, 2021, 912: 174562.
[2] SICA A, ERRENI M, ALLAVENA P, et al. Macrophage polarization in pathology[J]. Cell Mol Life Sci, 2015, 72(21): 4111-4126.
[3] LIU Y, WANG J Y, LUO S Y, et al. The roles of PPARγ and its agonists in autoimmune diseases: a comprehensive review[J]. J Autoimmun, 2020, 113: 102510.
[4] KUMAR D P, CAFFREY R, MARIONEAUX J, et al. The PPAR α/γ agonist saroglitazar improves insulin resistance and steatohepatitis in a diet induced animal model of nonalcoholic fatty liver disease[J]. Sci Rep, 2020, 10(1): 9330.
[5] 吴燕, 张定然, 王新慧, 等. 巨噬细胞极化及其对炎性疾病作用的研究进展[J]. 中国畜牧杂志, 2021, 57(7): 22-26.
[6] PARISI L, GINI E, BACI D, et al. Macrophage polarization in chronic inflammatory diseases: killers or builders?[J]. J Immunol Res, 2018, 2018: 8917804.
[7] 周琦, 孙慧娟, 于栋华, 等. 巨噬细胞M1/M2型极化在不同疾病中的作用机制[J]. 中国药理学通报, 2020, 36(11): 1502-1506.
[8] GARLET G P, GIANNOBILE W V. Macrophages: the bridge between inflammation resolution and tissue repair?[J]. J Dent Res, 2018, 97(10): 1079-1081.
[9] ZHOU J W, TANG Z W, GAO S Y, et al. Tumor-associated macrophages: recent insights and therapies[J]. Front Oncol, 2020, 10: 188.
[10] 王宇驰, 栾志勇, 孙璐璐, 等. 肿瘤相关巨噬细胞生物学作用研究进展[J]. 延边大学医学学报, 2021, 44(3): 228-232.
[11] WAGNER N, WAGNER K D. The role of PPARs in disease[J]. Cells, 2020, 9(11): 2367.
[12] 陈超, 张瑞芬, 张海荣. PPAR-γ与动脉粥样硬化及其危险因素的相关研究进展[J]. 中国循证心血管医学杂志, 2021, 13(9): 1146-1147.
[13] MARION-LETELLIER R, SAVOYE G, GHOSH S. Fatty acids, eicosanoids and PPAR gamma[J]. Eur J Pharmacol, 2016, 785: 44-49.
[14] SHI Y J, ZOU Y X, SHEN Z Y, et al. Trace elements, PPARs, and metabolic syndrome[J]. Int J Mol Sci, 2020, 21(7): 2612.
[15] BUSCH D, KAPOOR A, RADEMANN P, et al. Delayed activation of PPAR-β/δ improves long-term survival in mouse Sepsis: effects on organ inflammation and coagulation[J]. Innate Immun, 2018, 24(4): 262-273.
[16] YOUSEFNIA S, MOMENZADEH S, SEYED FOROOTAN F, et al. The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity[J]. Gene, 2018, 649: 14-22.
[17] SCHNEIDER C, NOBS S P, KURRER M, et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages[J]. Nat Immunol, 2014, 15(11): 1026-1037.
[18] 赵九洲, 姜晓旭, 李宏伟, 等. JAK-STAT信号通路与巨噬细胞炎症调控的研究进展[J]. 癌变·畸变·突变, 2020, 32(5): 402-404, 408.
[19] RICOTE M, LI A C, WILLSON T M, et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation[J]. Nature, 1998, 391(6662): 79-82.
[20] 任凯旋, 涂岳圣, 朱涛, 等. 大黄素通过PPARγ/NF-κB信号通路抑制LPS诱导的RAW_264.7细胞炎症反应[J]. 西部医学, 2018, 30(1): 12-15, 20.
[21] CHOI M J, LEE E J, PARK J S, et al. Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: critical role of PPAR-γ signaling pathway[J]. Biochem Pharmacol, 2017, 144: 120-131.
[22] KRATZ M, COATS B R, HISERT K B, et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages[J]. Cell Metab, 2014, 20(4): 614-625.
[23] CHARO I F. Macrophage polarization and insulin resistance: PPARgamma in control[J]. Cell Metab, 2007, 6(2): 96-98.
[24] ODEGAARD J I, RICARDO-GONZALEZ R R, GOFORTH M H, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance[J]. Nature, 2007, 447(7148): 1116-1120.
[25] JUN I, KIM B R, PARK S Y, et al. Interleukin-4 stimulates lipogenesis in meibocytes by activating the STAT6/PPARγ signaling pathway[J]. Ocul Surf, 2020, 18(4): 575-582.
[26] YAO Q Y, LIU J, ZHANG Z H, et al. Peroxisome proliferator-activated receptor γ (PPARγ) induces the gene expression of integrin αVβ5 to promote macrophage M2 polarization[J]. J Biol Chem, 2018, 293(43): 16572-16582.
[27] SINGLA B, HOLMDAHL R, CSANYI G. Editorial: oxidants and redox signaling in inflammation[J]. Front Immunol, 2019, 10: 545.
[28] BRÜNE B, DEHNE N, GROSSMANN N, et al. Redox control of inflammation in macrophages[J]. Antioxid Redox Signal, 2013, 19(6): 595-637.
[29] RENDRA E, RIABOV V, MOSSEL D M, et al. Reactive oxygen species (ROS) in macrophage activation and function in diabetes[J]. Immunobiology, 2019, 224(2): 242-253.
[30] DANIEL B, NAGY G, CZIMMERER Z, et al. The nuclear receptor PPARγ controls progressive macrophage polarization as a ligand-insensitive epigenomic ratchet of transcriptional memory[J]. Immunity, 2018, 49(4): 615-626.e6.
[31] 王欣. ROS对胰岛素分泌、利用障碍及其关键分子的调控与干预机制[D]. 西安: 第四军医大学, 2012.
[32] DAS N R, VAIDYA B, KHARE P, et al. Combination of peroxisome proliferator-activated receptor gamma (PPARγ) agonist and PPAR gamma co-activator 1α (PGC-1α) activator ameliorates cognitive deficits, oxidative stress, and inflammation in rodent model of Parkinson's disease[J]. Curr Neurovasc Res, 2021, 18(5): 497-507.
[33] DE AZAMBUJA G, JORGE C O, GOMES B B, et al. Regular swimming exercise prevented the acute and persistent mechanical muscle hyperalgesia by modulation of macrophages phenotypes and inflammatory cytokines via PPARγ receptors[J]. Brain Behav Immun, 2021, 95: 462- 476.
[34] HU L Q, CHEN H, ZHANG X L, et al. Rosiglitazone ameliorates radiation-induced intestinal inflammation in rats by inhibiting NLRP3 inflammasome and TNF-α production[J]. J Radiat Res, 2020, 61(6): 842-850.
[35] 成家飞, 徐艺, 顾培青, 等. PPAR-γ在三硝基苯磺酸诱导的肠纤维化模型小鼠结肠中的动态表达特点[J]. 现代中西医结合杂志, 2021, 30(34): 3763-3768, 3782.
[36] CHEN Y, YANG B, STANTON C, et al. Bifidobacterium pseudocatenulatum ameliorates DSS-induced colitis by maintaining intestinal mechanical barrier, blocking proinflammatory cytokines, inhibiting TLR4/NF-κB signaling, and altering gut microbiota[J]. J Agric Food Chem, 2021, 69(5): 1496-1512.
[37] TIAN X L, PENG Z L, LUO S P, et al. Aesculin protects against DSS-Induced colitis though activating PPARγ and inhibiting NF-кB pathway [J]. Eur J Pharmacol, 2019, 857: 172453.
[38] DEROSA G, SAHEBKAR A, MAFFIOLI P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice[J]. J Cell Physiol, 2018, 233(1): 153-161.
[39] KAPLAN J M, ZINGARELLI B, KRALLMAN K, et al. Phase 1 safety and pharmacokinetic study on the use of pioglitazone in critically ill patients with Sepsis: a randomized clinical trial[J]. Intensive Care Med, 2018, 44(11): 2006-2008.
[40] MURAKAMI-NISHIDA S, MATSUMURA T, SENOKUCHI T, et al. Pioglitazone suppresses macrophage proliferation in apolipoprotein- E deficient mice by activating PPARγ[J]. Atherosclerosis, 2019, 286: 30- 39.
[41] LIU Y, QU Y, LIU L, et al. PPAR-γ agonist pioglitazone protects against IL-17 induced intervertebral disc inflammation and degeneration via suppression of NF-κB signaling pathway[J]. Int Immunopharmacol, 2019, 72: 138-147.
[42] YEMCHENKO Y O, SHYNKEVYCH V I, ISHCHEIKIN K Y, et al. PPAR-gamma agonist pioglitazone reduced CD68+ but not CD163+ macrophage dermal infiltration in obese psoriatic patients[J]. PPAR Res, 2020, 2020: 4548012.
[43] SHOKOUH P, JOHARIMOGHADAM A, ROOHAFZA H, et al. Effects of pioglitazone on asymmetric dimethylarginine and components of the metabolic syndrome in nondiabetic patients (EPICAMP study): a double-blind, randomized clinical trial[J]. PPAR Res, 2013, 2013: 358074.