The role of macrophage-to-myofibroblast transition in renal fibrosis

doi:10.3877/cma.j.issn.1674-3903.2024.03.007

Abstract

Abstract:

Renal fibrosis is the primary pathological change during the progression of chronic kidney disease, leading to severe damage to kidney structure and function. Macrophage-to-myofibroblast transition (MMT) is a core element in the development of renal fibrosis, occurring in an environment of chronic inflammatory stress, where bone marrow-derived macrophages differentiate into myofibroblasts, thus promoting the progression of renal fibrosis. This article reviews the research progress and mechanisms of MMT in kidney fibrosis, focusing on the role of transforming growth factor-β1/Smad3 signaling pathway, Janus kinase 3/signal transducer and activator of transcription 6 signaling pathway, and the role of M1 and M2 macrophages in MMT. Furthermore, this article also comprehensively presents current treatment strategies, including pharmacological treatments targeting specific signaling pathways and emerging therapeutic strategies, showing the latest advancements in the field of renal fibrosis treatment.

Key words: Macrophage, Macrophage-to-myofibroblast transition, Renal fibrosis, Myofibroblast, M2 macrophage

Zhuocheng Li, Yuxiang Chen, Liang Gao, Yu Zhang, Xuyuan Zhu, Xiaojie Ma, Tao Li, Tiantian Zhao, Hongtao Jiang. The role of macrophage-to-myofibroblast transition in renal fibrosis[J]. Chinese Journal of Transplantation(Electronic Edition), 2024, 18(03): 181-185.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhyzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-3903.2024.03.007

https://zhyzzz.cma-cmc.com.cn/EN/Y2024/V18/I03/181

References 45

1	Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease - a systematic review and meta-analysis[J]. PLoS One, 2016, 11(7): e0158765.
2	Webster AC, Nagler EV, Morton RL, et al. Chronic kidney disease[J]. Lancet, 2017, 389(10075): 1238-1252.
3	Shook BA, Wasko RR, Rivera-Gonzalez GC, et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair[J]. Science, 2018, 362(6417): eaar2971.
4	Kuppe C, Ibrahim MM, Kranz J, et al. Decoding myofibroblast origins in human kidney fibrosis[J]. Nature, 2021, 589(7841): 281-286.
5	Tang PM, Nikolic-Paterson DJ, Lan HY. Macrophages: versatile players in renal inflammation and fibrosis[J]. Nat Rev Nephrol, 2019, 15(3): 144-158.
6	Hewitson TD, Holt SG, Smith ER. Progression of tubulointerstitial fibrosis and the chronic kidney disease phenotype - role of risk factors and epigenetics[J]. Front Pharmacol, 2017, 8: 520.
7	Wang M, Xu H, Li Y, et al. Exogenous bone marrow derived-putative endothelial progenitor cells attenuate ischemia reperfusion-induced vascular injury and renal fibrosis in mice dependent on pericytes[J]. Theranostics, 2020, 10(26): 12144-12157.
8	Tanaka S, Portilla D, Okusa MD. Role of perivascular cells in kidney homeostasis, inflammation, repair and fibrosis[J]. Nat Rev Nephrol, 2023，19(11): 721-732.
9	Jordan NP, Tingle SJ, Shuttleworth VG, et al. MiR-126-3p is dynamically regulated in endothelial-to-mesenchymal transition during fibrosis[J]. Int J Mol Sci, 2021, 22(16): 8629.
10	Vierhout M, Ayoub A, Naiel S, et al. Monocyte and macrophage derived myofibroblasts: is it fate? A review of the current evidence[J]. Wound Repair Regen, 2021, 29(4): 548-562.
11	LeBleu VS, Taduri G, O′Connell J, et al. Origin and function of myofibroblasts in kidney fibrosis[J]. Nat Med, 2013, 19(8): 1047-1053.
12	Meng XM, Wang S, Huang XR, et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis[J]. Cell Death Dis, 2016, 7(12): e2495.
13	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.
14	Wei J, Xu Z, Yan X. The role of the macrophage-to-myofibroblast transition in renal fibrosis[J]. Front Immunol, 2022, 13: 934377.
15	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.
16	Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity[J]. Annu Rev Pathol, 2020, 15: 123-147.
17	Christofides A, Strauss L, Yeo A, et al. The complex role of tumor-infiltrating macrophages[J]. Nat Immunol, 2022, 23(8): 1148-1156.
18	Li X, Wu J, Zhu S, et al. Intragraft immune cells: accomplices or antagonists of recipient-derived macrophages in allograft fibrosis？[J]. Cell Mol Life Sci, 2023, 80(7): 195.
19	Liu B, Jiang J, Liang H, et al. Natural killer T cell/IL-4 signaling promotes bone marrow-derived fibroblast activation and M2 macrophage-to-myofibroblast transition in renal fibrosis[J]. Int Immunopharmacol, 2021, 98: 107907.
20	Liang H, Liu B, Gao Y, et al. Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis[J]. Front Immunol, 2022, 13: 978262.
21	Qiang P, Hao J, Yang F, et al. Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-beta1 pathway in mice induced with aldosterone[J]. Front Immunol, 2022, 13: 948658.
22	Su J, Morgani SM, David CJ, et al. TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1[J]. Nature, 2020, 577(7791): 566-571.
23	Yuan Q, Tang B, Zhang C. Signaling pathways of chronic kidney diseases, implications for therapeutics[J]. Signal Transduct Target Ther, 2022, 7(1): 182.
24	Zhang Y, Jin D, Kang X, et al. Signaling pathways involved in diabetic renal fibrosis[J]. Front Cell Dev Biol, 2021, 9: 696542.
25	Zou LL, Li JR, Li H, et al. TGF-β isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling pathway dependent and independent manners[J]. J Cell Mol Med, 2021, 25(7): 3498-3510.
26	Gifford CC, Tang J, Costello A, et al. Negative regulators of TGF-β1 signaling in renal fibrosis; pathological mechanisms and novel therapeutic opportunities[J]. Clin Sci (Lond), 2021, 135(2): 275-303.
27	Vander Ark A, Cao J, Li X. TGF-β receptors: in and beyond TGF-β signaling[J]. Cell Signal, 2018, 52: 112-120.
28	Lin Z, Chen A, Cui H, et al. Renal tubular epithelial cell necroptosis promotes tubulointerstitial fibrosis in patients with chronic kidney disease[J]. FASEB J, 2022, 36(12): e22625.
29	Xiao Y, Jiang X, Peng C, et al. BMP-7/Smads-induced inhibitor of differentiation 2 (Id2) upregulation and Id2/Twist interaction was involved in attenuating diabetic renal tubulointerstitial fibrosis[J]. Int J Biochem Cell Biol, 2019, 116: 105613.
30	Chen J, Xia Y, Lin X, et al. Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis[J]. Lab Invest, 2014, 94(5): 545-556.
31	Wang Y, Li Y, Chen Z, et al. GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy[J]. Cell Death Dis, 2022, 13(8): 693.
32	Espinosa Gonzalez M, Volk-Draper L, Bhattarai N, et al. Th2 cytokines IL-4, IL-13, and IL-10 promote differentiation of pro-lymphatic progenitors derived from bone marrow myeloid precursors[J]. Stem Cells Dev, 2022, 31(11-12): 322-333.
33	Yan J, Zhang Z, Yang J, et al. JAK3/STAT6 Stimulates bone marrow-derived fibroblast activation in renal fibrosis[J]. J Am Soc Nephrol, 2015, 26(12): 3060-3071.
34	Zhou X, Chen H, Hu Y, et al. Enhancer of zeste homolog 2 promotes renal fibrosis after acute kidney injury by inducing epithelial-mesenchymal transition and activation of M2 macrophage polarization[J]. Cell Death Dis, 2023, 14(4): 253.
35	Lee YJ, Kim K, Kim M, et al. Inhibition of STAT6 activation by AS1517499 inhibits expression and activity of PPARγ in macrophages to resolve acute inflammation in mice[J]. Biomolecules, 2022, 12(3): 447.
36	Yuan T, Xia Y, Pan S, et al. STAT6 promoting oxalate crystal deposition-induced renal fibrosis by mediating macrophage-to-myofibroblast transition via inhibiting fatty acid oxidation[J]. Inflamm Res, 2023, 72(12): 2111-2126.
37	Shu H, Wang Y, Zhang H, et al. The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease[J]. Front Pharmacol, 2023, 14: 1169054.
38	Feng Y, Guo F, Xia Z, et al. Inhibition of fatty acid-binding protein 4 attenuated kidney fibrosis by mediating macrophage-to-myofibroblast transition[J]. Front Immunol, 2020, 11: 566535.
39	Chen J, Tang Y, Zhong Y, et al. P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition[J]. Mol Ther, 2022, 30(9): 3017-3033.
40	Tang PM, Zhang YY, Xiao J, et al. Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition[J]. Proc Natl Acad Sci U S A, 2020, 117(34): 20741-20752.
41	Xiong Y, Chang Y, Hao J, et al. Eplerenone attenuates fibrosis in the contralateral kidney of UUO rats by preventing macrophage-to-myofibroblast transition[J]. Front Pharmacol, 2021, 12: 620433.
42	Luo L, Wang S, Hu Y, et al. Precisely regulating M2 subtype macrophages for renal fibrosis resolution[J]. ACS Nano, 2023, 17(22): 22508-22526.
43	Feng Y, Guo F, Mai H, et al. Pterostilbene, a bioactive component of blueberries, alleviates renal interstitial fibrosis by inhibiting macrophage-myofibroblast transition[J]. Am J Chin Med, 2020, 48(7): 1715-1729.
44	Yunzhao X, Lingjin L, Ziqian L, et al. Huoxue Jiedu Huayu recipe alleviates contralateral renal fibrosis in unilateral ureteral obstruction rats by inhibiting the transformation of macrophages to myofibroblast[J]. J Tradit Chin Med, 2023, 43(1): 105-112.
45	Xianyuan L, Wei Z, Yaqian D, et al. Anti-renal fibrosis effect of asperulosidic acid via TGF-β1/smad2/smad3 and NF-κB signaling pathways in a rat model of unilateral ureteral obstruction[J]. Phytomedicine, 2019, 53: 274-285.

[1]	Lulu Li, Lihong Ma, Jiajia Jin, Wei Gu. Stimulator of interferon genes affects acute lung injury repair in mice through pulmonary macrophage efferocytosis [J]. Chinese Journal of Critical Care Medicine(Electronic Edition), 2024, 17(02): 97-103.
[2]	Jiayi Xue, Li Wang, Tao Ai. Current research progress on mechanism of macrophages in children with Mycoplasma pneumoniae pneumonia [J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2023, 19(06): 643-648.
[3]	Yixian Lu, Zhentao Zhang, Demeng Xia, Jialin Wang. Research progress of the regulating role and mechanism of macrophage polarization in osteoporosis [J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2023, 18(06): 538-541.
[4]	Peng Wang, Houan Xiao, Chiyu Jia. Research progress of different factors regulating macrophage polarization in chronic refractory wound [J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2023, 18(05): 454-459.
[5]	Jingyi Di, Yujiang Chen, Xinxin Chen, Wenxia Chen. Effect of stromal cell-derived factor 1 on macrophage polarization through PI3K/AKT1 signaling pathway [J]. Chinese Journal of Stomatological Research(Electronic Edition), 2024, 18(02): 89-95.
[6]	Yuan Zhang, Xiaolong Li, Yapeng Wang. Relationship between ANGPTL2 protein and immunosuppressive cell infiltration in pancreatic cancer and its clinical significance [J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Edition), 2023, 17(02): 145-148.
[7]	Yinqing Wo, Xiangqun Yang. The physiological function of cardiac macrophages and their role after myocardial infarction [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 167-171.
[8]	Yan Liu, Yaping Ye, Yanli Zheng. Interference with LINC00466 inhibits the malignant biological behavior of endometrial cancer RL95-2 cells through miR-493-3p/MIF [J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 151-158.
[9]	Huijie Zhou, Yunlong Zhang. Analysis of pathogenesis and treatment of renal fibrosis in traditional Chinese medicine based on data mining techniques [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2024, 13(03): 152-160.
[10]	Yansheng Jin, Gaiqin Dong, Xiaozhong Li. Progress of research on the role and mechanism of macrophages in vascular calcification of patients with chronic kidney disease [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(04): 234-237.
[11]	Qiong Wu, Guozhen Zhu. Bioinformatic analysis of genes associated with M2 macrophages in membranous nephropathy [J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2023, 12(03): 156-162.
[12]	Hanbing Chen, Cuilin Chu, Haibo Qiu. New insights in macrophage dying mechanisms in acute respiratory distress syndrome [J]. Chinese Journal of Critical Care & Intensive Care Medicine(Electronic Edition), 2024, 10(01): 79-84.
[13]	Zaixiang Li, Sugui Wang, Xianyun Zhang, Jianwen Lu, Hongsheng Ji, Fujin Jiang. A study of tumor-associated macrophages regalating the proliferation of human bladder cancer cells through TNF-α/B7H3 [J]. Chinese Journal of Clinicians(Electronic Edition), 2024, 18(01): 64-71.
[14]	Zhaoquan Liu, Fangfang Zhang, Honghao Song, Gang Wang, Mingyu Cui. Diagnostic features of intraperitoneal inflammatory myofibroblastic tumor in children and literature review [J]. Chinese Journal of Diagnostics(Electronic Edition), 2024, 12(02): 101-106.
[15]	Shihao Li, Yujiao Wang, Zihao Li, Bin Wu, Yinliang Sheng, Yu Qi. Single cell transcriptome analysis of macrophage cap protein on proliferation and metastasis of esophageal squamous cell carcinoma cells [J]. Chinese Journal of Thoracic Surgery(Electronic Edition), 2023, 10(02): 98-105.

Please choose a citation manager

Content to export