巨噬细胞在移植肾纤维化中的作用研究进展

任滌非; 王於尘; 苗芸

doi:10.3969/j.issn.1674-7445.2023084

巨噬细胞在移植肾纤维化中的作用研究进展

doi: 10.3969/j.issn.1674-7445.2023084

任滌非^{1, 2,},
王於尘¹,
苗芸^1, ,

1.
510515　广州，南方医科大学南方医院器官移植科
2.
南方医科大学第一临床医学院

基金项目: 国家自然科学基金（82270784、82070770、82170767）；广东省基础与应用基础研究基金（2023A1515012276）；大学生创新创业训练计划项目（202212121242）

详细信息

作者简介:

通讯作者:
苗芸（ORCID：0000-0003-3592-4695），博士，主任医师，研究方向为肾移植，Email：miaoyunecho@126.com

中图分类号: R617, R329.2
计量
- 文章访问数: 350
- HTML全文浏览量: 174
- PDF下载量: 62
- 被引次数: 0
出版历程
- 收稿日期: 2023-04-16
- 录用日期: 2023-07-07
- 网络出版日期: 2023-07-20
- 刊出日期: 2023-09-15

Research progress on the role of macrophages in renal allograft fibrosis

Ren Difei^{1, 2
,},
Wang Yuchen¹,
Miao Yun^{1
, ,}

1.
Department of Organ Transplantation, Nanfang Hospital of Southern Medical University, Guangzhou 510515, China

More Information

Corresponding author: Miao Yun, Email: miaoyunecho@126.com

摘要

摘要: 缺血-再灌注损伤、排斥反应、钙调磷酸酶抑制剂造成的肾毒性等因素会在肾移植术后使肾细胞外基质过度积聚，逐渐造成移植肾纤维化，最终导致肾衰竭。近年来，巨噬细胞在移植肾纤维化中的作用机制逐渐受到关注，有研究表明哺乳动物雷帕霉素靶蛋白抑制剂等药物可以通过巨噬细胞途径减缓肾移植术后移植肾纤维化。本文就移植肾纤维化的主要病因及病理生理学机制、不同巨噬细胞在移植肾纤维化进展中的作用、外周募集巨噬细胞和肾驻留巨噬细胞对肾损伤区域的浸润、巨噬细胞对肌成纤维细胞的诱导作用及巨噬细胞相关的移植肾纤维化潜在治疗方案进行综述，以期为巨噬细胞在移植肾纤维化中的研究提供参考。
- 纤维化 /
- 肾移植 /
- 巨噬细胞 /
- 肌成纤维细胞 /
- 缺血-再灌注损伤 /
- 钙调磷酸酶抑制剂 /
- 炎症反应 /
- 排斥反应
Abstract: Ischemia-reperfusion injury, rejection, nephrotoxicity caused by calcineurin inhibitors and other factors cause excessive accumulation of renal extracellular matrix after kidney transplantation, which gradually induce renal fibrosis and eventually lead to renal failure. In recent years, the mechanism of macrophages in renal allograft fibrosis has gradually captivated widespread attention. Studies have shown that some drugs like mammalian target of rapamycin inhibitors may mitigate renal allograft fibrosis through the macrophage. In this article, the main pathogenesis and pathophysiological mechanism of renal allograft fibrosis, the role of different macrophages in the progression of renal allograft fibrosis, the infiltration of peripherally-recruited macrophages and renal resident macrophages into renal injury areas, the induction of myofibroblasts by macrophages and potential treatment regimens of macrophage-associated renal allograft fibrosis were reviewed, aiming to provide reference for investigating the role of macrophages in renal allograft fibrosis.
- Fibrosis /
- Kidney transplantation /
- Macrophage /
- Myofibroblasts /
- Ischemia-reperfusion injury /
- Calcineurin inhibitor /
- Inflammation /
- Rejection

HTML全文

下载: 全尺寸图片幻灯片

参考文献(50)

[1]	DOREILLE A, DIEUDÉ M, CARDINAL H. The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients[J]. Am J Physiol Renal Physiol, 2019, 316(1): F9-F19. DOI: 10.1152/ajprenal.00163.2018.
[2]	MAHTAL N, LENOIR O, TINEL C, et al. MicroRNAs in kidney injury and disease[J]. Nat Rev Nephrol, 2022, 8(10): 643-662. DOI: 10.1038/s41581-022-00608-6.
[3]	邹开燕, 王淑君, 姚翠微. 低氧诱导因子-1α的生物学功能及其在肾纤维化中作用的研究进展[J]. 当代医药论丛, 2022, 20(21): 49-52. DOI: 10.3969/j.issn.2095-7629.2022.21.016. ZOU KY, WANG SJ, YAO CW. Research progress on biological function of hypoxia-inducible factor-1α and its role in renal fibrosis[J]. Contemp Med Forum, 2022, 20(21): 49-52. DOI: 10.3969/j.issn.2095-7629.2022.21.016.
[4]	CHANG FC, LIU CH, LUO AJ, et al. Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells[J]. Kidney Int, 2022, 102(4): 780-797. DOI: 10.1016/j.kint.2022.06.026.
[5]	SARITAS T, KRAMANN R. Kidney allograft fibrosis: diagnostic and therapeutic strategies[J]. Transplantation, 2021, 105(10): e114-e130. DOI: 10.1097/TP.0000000000003678.
[6]	HASSANEIN M, AUGUSTINE JJ. Chronic kidney transplant rejection[M]. Treasure Island (FL): StatPearls Publishing, 2023.
[7]	PAKSHIR P, HINZ B. The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication[J]. Matrix Biol, 2018, 68-69: 81-93. DOI: 10.1016/j.matbio.2018.01.019.
[8]	ZHOU D, LIU Y. Renal fibrosis in 2015: understanding the mechanisms of kidney fibrosis[J]. Nat Rev Nephrol, 2016, 12(2): 68-70. DOI: 10.1038/nrneph.2015.215.
[9]	LANGEWISCH E, MANNON RB. Chronic allograft injury[J]. Clin J Am Soc Nephrol, 2021, 16(11): 1723-1729. DOI: 10.2215/CJN.15590920.
[10]	WEISKIRCHEN R, WEISKIRCHEN S, TACKE F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications[J]. Mol Aspects Med, 2019, 65: 2-15. DOI: 10.1016/j.mam.2018.06.003.
[11]	YANG B, SHI D, CHEN Y, et al. The potential diagnostic value of immune-related genes in interstitial fibrosis and tubular atrophy after kidney transplantation[J]. J Immunol Res, 2022: 7212852. DOI: 10.1155/2022/7212852.
[12]	PANZER SE. Macrophages in transplantation: a matter of plasticity, polarization, and diversity[J]. Transplantation, 2022, 106(2): 257-267. DOI: 10.1097/TP.0000000000003804.
[13]	PORTILLA D, XAVIER S. Role of intracellular complement activation in kidney fibrosis[J]. Br J Pharmacol, 2021, 178(14): 2880-2891. DOI: 10.1111/bph.15408.
[14]	王永康, 李佳怡, 关飞, 等. 巨噬细胞极化机制及其在常见疾病中的作用[J]. 热带病与寄生虫学, 2022, 20(2): 103-108, 112. DOI: 10.3969/j.issn.1672-2302.2022.02.013. WANG YK, LI JY, GUAN F, et al. Mechanisms of macrophage polarization and its role in common diseases[J]. J Trop Dis Parasitol, 2022, 20(2): 103-108, 112. DOI: 10.3969/j.issn.1672-2302.2022.02.013.
[15]	邓格, 豆猛, 宫惠琳, 等. 肾移植术后抗体介导排斥反应中不同亚型的巨噬细胞浸润分析[J/CD]. 实用器官移植电子杂志, 2022, 10(4): 320-325. DOI: 10.3969/j.issn.2095-5332.2022.04.006. DENG G, DOU M, GONG HL, et al. Analysis of different subtypes of macrophages infiltrated in kidney allografts with antibody mediated rejection[J/CD]. Pract J Organ Transplant (Electr Vers), 2022, 10(4): 320-325. DOI: 10.3969/j.issn.2095-5332.2022.04.006.
[16]	DEVRAJ VM, KALIDINDI K, GUDITI S, et al. Macrophage polarization in kidney transplant patients[J]. Transpl Immunol, 2022, 75: 101717. DOI: 10.1016/j.trim.2022.101717.
[17]	TANG PM, NIKOLIC-PATERSON DJ, LAN HY. Macrophages: versatile players in renal inflammation and fibrosis[J]. Nat Rev Nephrol, 2019, 15(3): 144-158. DOI: 10.1038/s41581-019-0110-2.
[18]	HUEN SC, CANTLEY LG. Macrophages in renal injury and repair[J]. Annu Rev Physiol, 2017, 79: 449-469. DOI: 10.1146/annurev-physiol-022516-034219.
[19]	AIELLO S, PODESTÀ MA, RODRIGUEZ-ORDONEZ PY, et al. Transplantation-induced ischemia-reperfusion injury modulates antigen presentation by donor renal CD11c⁺F4/80⁺ macrophages through IL-1R8 regulation[J]. J Am Soc Nephrol, 2020, 31(3): 517-531. DOI: 10.1681/ASN.2019080778.
[20]	TOKI D, ZHANG W, HOR KL, et al. The role of macrophages in the development of human renal allograft fibrosis in the first year after transplantation[J]. Am J Transplant, 2014, 14(9): 2126-2136. DOI: 10.1111/ajt.12803.
[21]	TANG L, ZHANG H, WANG C, et al. M2A and M2C macrophage subsets ameliorate inflammation and fibroproliferation in acute lung injury through interleukin 10 pathway[J]. Shock, 2017, 48(1): 119-129. DOI: 10.1097/SHK.0000000000000820.
[22]	WANG S, MENG XM, NG YY, et al. TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis[J]. Oncotarget, 2016, 7(8): 8809-8822. DOI: 10.18632/oncotarget.6604.
[23]	MEHRABI A, FONOUNI H, AYOUB E, et al. A single center experience of combined liver kidney transplantation[J]. Clin Transplant, 2009, 23(Suppl 21): 102-114. DOI: 10.1111/j.1399-0012.2009.01146.x.
[24]	MENG XM, MAK TS, LAN HY. Macrophages in renal fibrosis[J]. Adv Exp Med Biol, 2019, 1165: 285-303. DOI: 10.1007/978-981-13-8871-2_13.
[25]	王鑫瑶, 邓振领, 王悦. 单细胞RNA测序在肾脏领域的研究进展[J]. 临床肾脏病杂志, 2021, 21(2): 153-157. DOI: 10.3969/j.issn.1671-2390.y20-092. WANG XY, DENG ZL, WANG Y. Research advances of single-cell RNA sequencing in kidney[J]. J Clin Nephrol, 2021, 21(2): 153-157. DOI: 10.3969/j.issn.1671-2390.y20-092.
[26]	BRAGA TT, CORREA-COSTA M, SILVA RC, et al. CCR2 contributes to the recruitment of monocytes and leads to kidney inflammation and fibrosis development[J]. Inflammopharmacology, 2018, 26(2): 403-411. DOI: 10.1007/s10787-017-0317-4.
[27]	KANG YS, LEE MH, SONG HK, et al. CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice[J]. Kidney Int, 2010, 78(9): 883-894. DOI: 10.1038/ki.2010.263.
[28]	LI L, HUANG L, SUNG SS, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury[J]. Kidney Int, 2008, 74(12): 1526-1537. DOI: 10.1038/ki.2008.500.
[29]	DICK SA, WONG A, HAMIDZADA H, et al. Three tissue resident macrophage subsets coexist across organs with conserved origins and life cycles[J]. Sci Immunol, 2022, 7(67): eabf7777. DOI: 10.1126/sciimmunol.abf7777.
[30]	YANG Q, WANG Y, PEI G, et al. Bone marrow-derived Ly6C⁻ macrophages promote ischemia-induced chronic kidney disease[J]. Cell Death Dis, 2019, 10(4): 291. DOI: 10.1038/s41419-019-1531-3.
[31]	SANCHEZ-NIÑO MD, SANZ AB, ORTIZ A. Chronicity following ischaemia-reperfusion injury depends on tubular-macrophage crosstalk involving two tubular cell-derived CSF-1R activators: CSF-1 and IL-34[J]. Nephrol Dial Transplant, 2016, 31(9): 1409-1416. DOI: 10.1093/ndt/gfw026.
[32]	SALEI N, RAMBICHLER S, SALVERMOSER J, et al. The kidney contains ontogenetically distinct dendritic cell and macrophage subtypes throughout development that differ in their inflammatory properties[J]. J Am Soc Nephrol, 2020, 31(2): 257-278. DOI: 10.1681/ASN.2019040419.
[33]	WEI J, XU Z, YAN X. The role of the macrophage-to-myofibroblast transition in renal fibrosis[J]. Front Immunol, 2022, 13: 934377. DOI: 10.3389/fimmu.2022.934377.
[34]	ZHAO H, DONG Y, TIAN X, et al. Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases[J]. World J Nephrol, 2013, 2(3): 84-89. DOI: 10.5527/wjn.v2.i3.84.
[35]	TAN TK, ZHENG G, HSU TT, et al. Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage[J]. Lab Invest, 2013, 93(4): 434-449. DOI: 10.1038/labinvest.2013.3.
[36]	CHARREAU B. Cellular and molecular crosstalk of graft endothelial cells during AMR: effector functions and mechanisms[J]. Transplantation, 2021, 105(11): e156-e167. DOI: 10.1097/TP.0000000000003741.
[37]	WANG YY, JIANG H, PAN J, et al. Macrophage-to-myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury[J]. J Am Soc Nephrol, 2017, 28(7): 2053-2067. DOI: 10.1681/ASN.2016050573.
[38]	SCHAUERTE C, HÜBNER A, RONG S, et al. Antagonism of profibrotic microRNA-21 improves outcome of murine chronic renal allograft dysfunction[J]. Kidney Int, 2017, 92(3): 646-656. DOI: 10.1016/j.kint.2017.02.012.
[39]	MCDANIELS JM, SHETTY AC, KUSCU C, et al. Single nuclei transcriptomics delineates complex immune and kidney cell interactions contributing to kidney allograft fibrosis[J]. Kidney Int, 2023, 103(6): 1077-1092. DOI: 10.1016/j.kint.2023.02.018.
[40]	CELIE JW, KATTA KK, ADEPU S, et al. Tubular epithelial syndecan-1 maintains renal function in murine ischemia/reperfusion and human transplantation[J]. Kidney Int, 2012, 81(7): 651-661. DOI: 10.1038/ki.2011.425.
[41]	江静,李虎,彭宗根. 肝内巨噬细胞在肝纤维化发展中的双重作用及其靶向治疗研究进展[J]. 中国药学杂志, 2021,56(23):1869-1873. DOI: 10.11669/cpj.2021.23.001. JIANG J, LI H, PENG ZG. Recent progress in study on the progressive and regressive roles of liver macrophage in hepatic fibrosis and its targeted drugs[J]. Chin Pharm J, 2021,56(23):1869-1873. DOI: 10.11669/cpj.2021.23.001.
[42]	刘青,王俊岩,邓波,等. 心阴片通过MLK3/JNK信号调控巨噬细胞极化改善慢性心力衰竭心肌纤维化的机制[J]. 中华中医药杂志, 2021,36(10):6064-6068. LIU Q, WANG JY, DENG B, et al. Study on the role and mechanism of Xinyin Tablet against myocardial fibrosis in chronic heart failure based on MLK3/JNK signal regulating macrophage polarization[J]. China J Trad Chin Med Pharm, 2021,36(10):6064-6068.
[43]	周世琴,骆亚莉,周雯,等. 肺纤维化的相关分子机制和治疗现状[J]. 中国临床药理学与治疗学, 2022,27(10):1133-1147. DOI: 10.12092/j.issn.1009-2501.2022.10.008. ZHOU SQ, LUO YL, ZHOU W, et al. Molecular mechanism and treatment of pulmonary fibrosis[J]. Chin J Clin Pharm Ther, 2022,27(10):1133-1147. DOI: 10.12092/j.issn.1009-2501.2022.10.008.
[44]	杨迷玲,徐宪伟,张果,等. M2型巨噬细胞在移植肾上皮-间质转化中的作用[J]. 现代泌尿外科杂志, 2019,24(4):305-308,313. DOI: 10.3969/j.issn.1009-8291.2019.04.014. YANG ML, XU XW, ZHANG G, et al. The role of M2-type macrophages in epithelial-mesenchymal transition of kidney allograft[J]. J Mod Urol, 2019,24(4):305-308,313. DOI: 10.3969/j.issn.1009-8291.2019.04.014.
[45]	KONG G, CHEN Y, LIU Z, et al. Adenovirus-IL-10 relieves chronic rejection after mouse heart transplantation by inhibiting miR-155 and activating SOCS5[J]. Int J Med Sci, 2023, 20(2): 172-185. DOI: 10.7150/ijms.77093.
[46]	XIE Y, HU X, LI S, et al. Pharmacological targeting macrophage phenotype via gut-kidney axis ameliorates renal fibrosis in mice[J]. Pharmacol Res, 2022, 178: 106161. DOI: 10.1016/j.phrs.2022.106161.
[47]	SHIGEMATSU T, TAJIMA S, FU R, et al. The mTOR inhibitor everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats[J]. Life Sci, 2022, 288: 120150. DOI: 10.1016/j.lfs.2021.120150.
[48]	LAI C, CHADBAN SJ, LOH YW, et al. Targeting inflammatory monocytes by immune-modifying nanoparticles prevents acute kidney allograft rejection[J]. Kidney Int, 2022, 102(5): 1090-1102. DOI: 10.1016/j.kint.2022.06.024.
[49]	ZHOU L, XUE X, HOU Q, et al. Targeting ferroptosis attenuates interstitial inflammation and kidney fibrosis[J]. Kidney Dis (Basel), 2021, 8(1): 57-71. DOI: 10.1159/000517723.
[50]	ZHENG H, ZHANG Y, HE J, et al. Hydroxychloroquine inhibits macrophage activation and attenuates renal fibrosis after ischemia-reperfusion injury[J]. Front Immunol, 2021, 12: 645100. DOI: 10.3389/fimmu.2021.645100.