TREM2 in Macrophages Promotes Renal Fibrosis via Activation of β-Catenin Signalling Pathway in Obstructive Nephropathy

Abstract

Obstructive nephropathy leads to renal fibrosis, and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) drives this macrophage-mediated process, but its mechanism remains unclear. This study investigated TREM2's role in macrophage polarisation and renal fibrosis progression. In human fibrotic kidneys, TREM2 expression was significantly elevated and co-localised with macrophages. Unilateral ureteral obstruction (UUO) modelling in mice recapitulated this upregulation, accompanied by renal fibrosis, M2 macrophage polarisation and glomerular filtration rate (GFR) reduction. Trem2 deficiency (Trem2^−/−) significantly attenuated these pathological changes in UUO mice, preserving GFR. Separately, TREM2 inhibitory peptide sequence IA9 administration reduced renal fibrosis and M2 polarisation in UUO mice. In bone marrow-derived macrophages (BMDMs), Trem2 deficiency suppressed IL-4/IL-13-induced M2 polarisation, migration and β-catenin expression. Critically, lithium chloride (LiCl)-mediated β-catenin stabilisation rescued these impairments in Trem2^−/− BMDMs. In conclusion, TREM2 promotes renal fibrosis by activating β-catenin signalling to drive profibrotic M2 macrophage responses, establishing TREM2 blockade as a therapeutic strategy for obstructive nephropathy.

Keywords

macrophage / obstructive nephropathy / renal fibrosis / TREM2

References

[1] S. E. Ingraham and K. M. McHugh, “Current Perspectives on Congenital Obstructive Nephropathy,” Pediatric Nephrology 26, no. 9 (2011): 1453–1461.

[2] R. L. Chevalier, B. A. Thornhill, M. S. Forbes, and S. C. Kiley, “Mechanisms of Renal Injury and Progression of Renal Disease in Congenital Obstructive Nephropathy,” Pediatric Nephrology 25, no. 4 (2010): 687–697.

[3] B. Bikbov, C. A. Purcell, and A. S. Levey, “Global, Regional, and National Burden of Chronic Kidney Disease, 1990–2017: A Systematic Analysis for the Global Burden of Disease Study 2017,” Lancet 395, no. 10225 (2020): 709–733.

[4] R. J. Glassock, D. G. Warnock, and P. Delanaye, “The Global Burden of Chronic Kidney Disease: Estimates, Variability and Pitfalls,” Nature Reviews Nephrology 13, no. 2 (2016): 104–114.

[5] L. M. Black, J. M. Lever, and A. Agarwal, “Renal Inflammation and Fibrosis: A Double-Edged Sword,” Journal of Histochemistry and Cytochemistry 67, no. 9 (2019): 663–681.

[6] J. Wei, Z. Xu, and X. Yan, “The Role of the Macrophage-To-Myofibroblast Transition in Renal Fibrosis,” Frontiers in Immunology 13 (2022): 934377.

[7] P. Ramachandran, R. Dobie, J. R. Wilson-Kanamori, et al., “Resolving the Fibrotic Niche of Human Liver Cirrhosis at Single-Cell Level,” Nature 575, no. 7783 (2019): 512–518.

[8] Q. Luo, D. Deng, Y. Li, et al., “TREM2 Insufficiency Protects Against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization,” International Immunopharmacology 118 (2023): 110070.

[9] X. Gu, H. Kang, S. Cao, Z. Tong, and N. Song, “Blockade of TREM2 Ameliorates Pulmonary Inflammation and Fibrosis by Modulating Sphingolipid Metabolism,” Translational Research 275 (2025): 1–17.

[10] T. Hendrikx, F. Porsch, M. G. Kiss, et al., “Soluble TREM2 Levels Reflect the Recruitment and Expansion of TREM2+ Macrophages That Localize to Fibrotic Areas and Limit NASH,” Journal of Hepatology 77, no. 5 (2022): 1373–1385.

[11] D. Zhu, M. Huang, P. Shen, et al., “TREM2 Expression Promotes Liver and Peritoneal M2 Macrophage Polarization in Mice Infected With Schistosoma Japonicum,” Journal of Cellular and Molecular Medicine 27, no. 15 (2023): 2261–2269.

[12] I. Liebold, S. Meyer, M. Heine, et al., “TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes During the Progression of NAFLD,” Cells 12, no. 3 (2023): 341.

[13] Z. Xiao, Y. Wang, Y. Chen, et al., “Exosomes Derived From TREM-2 Knocked-Out Macrophages Alleviated Renal Fibrosis via HSPa1b/AKT Pathway,” American Journal of Physiology. Renal Physiology 328, no. 1 (2025): F131–F151.

[14] Y. Cui, C. Chen, Z. Tang, et al., “TREM2 Deficiency Aggravates Renal Injury by Promoting Macrophage Apoptosis and Polarization via the JAK-STAT Pathway in Mice,” Cell Death & Disease 15, no. 6 (2024): 401.

[15] R. Katayama, N. Yamaguchi, T. Yamashita, et al., “Calculation of Glomerular Filtration Rate in Conscious Rats by the Use of a Bolus Injection of Iodixanol and a Single Blood Sample,” Journal of Pharmacological and Toxicological Methods 61, no. 1 (2010): 59–64.

[16] D. Schock-Kusch, Q. Xie, Y. Shulhevich, et al., “Transcutaneous Assessment of Renal Function in Conscious Rats With a Device for Measuring FITC-Sinistrin Disappearance Curves,” Kidney International 79, no. 11 (2011): 1254–1258.

[17] M. Schetz and F. Schortgen, “Ten Shortcomings of the Current Definition of AKI,” Intensive Care Medicine 43, no. 6 (2017): 911–913.

[18] L. Liu, Y. Liu, Y. Xin, et al., “An Early and Stable Mouse Model of Polymyxin-Induced Acute Kidney Injury,” Intensive Care Medicine Experimental 12, no. 1 (2024): 88.

[19] A. Schreiber, Y. Shulhevich, S. Geraci, et al., “Transcutaneous Measurement of Renal Function in Conscious Mice,” American Journal of Physiology. Renal Physiology 303, no. 5 (2012): F783–F788.

[20] L. C. Racusen, K. Solez, R. B. Colvin, et al., “The Banff 97 Working Classification of Renal Allograft Pathology,” Kidney International 55, no. 2 (1999): 713–723.

[21] C. Roufosse, N. Simmonds, M. Clahsen-van Groningen, et al., “A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology,” Transplantation 102, no. 11 (2018): 1795–1814.

[22] Z. B. Zhao, J. A. Marschner, T. Iwakura, et al., “Tubular Epithelial Cell HMGB1 Promotes AKI-CKD Transition by Sensitizing Cycling Tubular Cells to Oxidative Stress: A Rationale for Targeting HMGB1 During AKI Recovery,” Journal of the American Society of Nephrology 34, no. 3 (2023): 394–411.

[23] A. Esparza-Baquer, I. Labiano, O. Sharif, et al., “TREM-2 Defends the Liver Against Hepatocellular Carcinoma Through Multifactorial Protective Mechanisms,” Gut 70, no. 7 (2021): 1345–1361.

[24] Z. Ansari, A. Chaurasia, and N. Sharma, “Exploring Inflammatory and Fibrotic Mechanisms Driving Diabetic Nephropathy Progression,” Cytokine & Growth Factor Reviews 84 (2025): 120–134.

[25] K. Otero, I. R. Turnbull, P. L. Poliani, et al., “Macrophage Colony-Stimulating Factor Induces the Proliferation and Survival of Macrophages via a Pathway Involving DAP12 and Beta-Catenin,” Nature Immunology 10, no. 7 (2009): 734–743.

[26] J. Wang, Z. Yan, W. Zhang, X. Liu, J. Wang, and Q. Peng, “Upregulation of TREM2 Expression in M2 Macrophages Promotes Brucella abortus Chronic Infection,” Frontiers in Immunology 15 (2024): 1466520.

[27] Y. Xin, Y. Liu, L. Liu, et al., “Dynamic Changes in the Real-Time Glomerular Filtration Rate and Kidney Injury Markers in Different Acute Kidney Injury Models,” Journal of Translational Medicine 22, no. 1 (2024): 857.

[28] M. S. Jensen, I. B. B. A. de Araujo, H. A. M. Mutsaers, and R. Nørregaard, “Transcutaneous Measurement of Renal Function in Two Rodent Models of Obstructive Nephropathy,” BMC Research Notes 16, no. 1 (2023): 119.

[29] A. B. Sigalov, “Inhibition of TREM-2 Markedly Suppresses Joint Inflammation and Damage in Experimental Arthritis,” International Journal of Molecular Sciences 23, no. 16 (2022): 8857.

[30] M. Molgora, E. Esaulova, W. Vermi, et al., “TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy,” Cell 182, no. 4 (2020): 886–900.

[31] R. L. Chevalier, M. S. Forbes, and B. A. Thornhill, “Ureteral Obstruction as a Model of Renal Interstitial Fibrosis and Obstructive Nephropathy,” Kidney International 75, no. 11 (2009): 1145–1152.

[32] L. Scarfe, D. Schock-Kusch, L. Ressel, et al., “Transdermal Measurement of Glomerular Filtration Rate in Mice,” Journal of Visualized Experiments 140 (2018): 58520.

[33] H. Zheng, L. Jia, C. C. Liu, et al., “TREM2 Promotes Microglial Survival by Activating Wnt/Beta-Catenin Pathway,” Journal of Neuroscience 37, no. 7 (2017): 1772–1784.

[34] W. Huang, B.-O. Wang, Y.-F. Hou, et al., “JAML Promotes Acute Kidney Injury Mainly Through a Macrophage-Dependent Mechanism,” JCI Insight 7, no. 14 (2022): e158571.

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2026 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.