Trem2 acts as a non-classical receptor of interleukin-4 to promote diabetic wound healing

Abstract

Background: The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage-related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established.

Objective: This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions.

Methods and results: Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage-specific knockout of Trem2 (T2-cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)-4 binds directly to Trem2, inactivating MAPK/AP-1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co-culture of fibroblasts and macrophages showed that macrophages from T2-cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing.

Conclusions: These analyses offer novel insight into the role of IL-4/Trem2 signalling as a mediator of myeloid cell-fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing.

Keywords

diabetic wound healing / IL-4 / macrophage / MAPK / Trem2

References

[1] Spampinato SF, Caruso GI, De Pasquale R, Sortino MA, Merlo S. The treatment of impaired wound healing in diabetes: looking among old drugs. Pharmaceuticals (Basel). 2020; 13(4): 60.

[2] Artasensi A, Pedretti A, Vistoli G, Fumagalli L. Type 2 diabetes mellitus: a review of multi-target drugs. Molecules. 2020; 25(8): 1987.

[3] Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018; 1411(1): 153-165.

[4] Kavitha KV, Tiwari S, Purandare VB, Khedkar S, Bhosale SS, Unnikrishnan AG. Choice of wound care in diabetic foot ulcer: a practical approach. World J Diabetes. 2014; 5(4): 546-556.

[5] Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed Pharmacother. 2019; 112: 108615.

[6] Kim SY, Nair MG. Macrophages in wound healing: activation and plasticity. Immunol Cell Biol. 2019; 97(3): 258-267.

[7] Minutti CM, Knipper JA, Allen JE, Zaiss DM. Tissue-specific contribution of macrophages to wound healing. Semin Cell Dev Biol. 2017; 61: 3-11.

[8] Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018; 9: 419.

[9] Buechler MB, Fu W, Turley SJ. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity. 2021; 54(5): 903-915.

[10] Vannella KM, Wynn TA. Mechanisms of organ injury and repair by macrophages. Annu Rev Physiol. 2017; 79: 593-617.

[11] Li RY, Qin Q, Yang HC, et al. TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target. Mol Neurodegener. 2022; 17(1): 40.

[12] Ulland TK, Colonna M. TREM2 – a key player in microglial biology and Alzheimer disease. Nat Rev Neurol. 2018; 14(11): 667-675.

[13] Painter MM, Atagi Y, Liu CC, et al. TREM2 in CNS homeostasis and neurodegenerative disease. Mol Neurodegener. 2015; 10: 43.

[14] Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron. 2016; 91(2): 328-340.

[15] Park M, Yi JW, Kim EM, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) promotes adipogenesis and diet-induced obesity. Diabetes. 2015; 64(1): 117-127.

[16] Jaitin DA, Adlung L, Thaiss CA, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019; 178(3): 686-698. e614.

[17] Wang X, He Q, Zhou C, et al. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity. 2023; 56(1): 58-77. e11.

[18] Seno H, Miyoshi H, Brown SL, Geske MJ, Colonna M, Stappenbeck TS. Efficient colonic mucosal wound repair requires Trem2 signaling. Proc Natl Acad Sci USA. 2009; 106(1): 256-261.

[19] Wiśniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods. 2009; 6(5): 359-362.

[20] Sharifiaghdam M, Shaabani E, Faridi-Majidi R, De Smedt SC, Braeckmans K, Fraire JC. Macrophages as a therapeutic target to promote diabetic wound healing. Mol Ther. 2022; 30(9): 2891-2908.

[21] Dardenne C, Salon M, Authier H, et al. Topical aspirin administration improves cutaneous wound healing in diabetic mice through a phenotypic switch of wound macrophages toward an anti-inflammatory and proresolutive profile characterized by LXA4 release. Diabetes. 2022; 71(10): 2181-2196.

[22] Kimball A, Schaller M, Joshi A, et al. Ly6C(Hi) blood monocyte/macrophage drive chronic inflammation and impair wound healing in diabetes mellitus. Arterioscler Thromb Vasc Biol. 2018; 38(5): 1102-1114.

[23] Sanyal S, Sandstrom DJ, Hoeffer CA, Ramaswami M. AP-1 functions upstream of CREB to control synaptic plasticity in Drosophila. Nature. 2002; 416(6883): 870-874.

[24] Toone WM, Morgan BA, Jones N. Redox control of AP-1-like factors in yeast and beyond. Oncogene. 2001; 20(19): 2336-2346.

[25] Yu Y, Wang Y, Niu Y, Fu L, Chin YE, Yu C. Leukemia inhibitory factor attenuates renal fibrosis through Stat3-miR-29c. Am J Physiol Ren Physiol. 2015; 309(7): F595-F603.

[26] Welc SS, Flores I, Wehling-Henricks M, et al. Targeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy. Nat Commun. 2019; 10(1): 2788.

[27] Jung SH, Hwang BH, Shin S, et al. Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2(hi) macrophages in infarcted hearts. Nat Commun. 2022; 13(1): 4580.

[28] Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877: 173090.

[29] Zhou X, Li W, Wang S, et al. YAP aggravates inflammatory bowel disease by regulating M1/M2 macrophage polarization and gut microbial homeostasis. Cell Rep. 2019; 27(4): 1176-1189. e1175.

[30] Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2-and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal. 2010; 3(122): ra38.

[31] Kober DL, Stuchell-Brereton MD, Kluender CE, et al. Functional insights from biophysical study of TREM2 interactions with apoE and Aβ(1-42). Alzheimers Dement. 2020; 3: 1-14.

[32] Xie X, Zhang W, Xiao M, et al. TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice. Blood. 2023; 141(26): 3184-3198.

[33] Zenz R, Eferl R, Scheinecker C, et al. Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res Ther. 2008; 10(1): 201.

[34] Schonthaler HB, Guinea-Viniegra J, Wagner EF. Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis. 2011; 70: i109-112. Suppl 1.

[35] Matthews CP, Colburn NH, Young MR. AP-1 a target for cancer prevention. Curr Cancer Drug Targets. 2007; 7(4): 317-324.

[36] Baumann D, Drebant J, Hagele T, et al. p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition. J Immunother Cancer. 2021; 9(7): e002319.

[37] Neamatallah T. Mitogen-activated protein kinase pathway: a critical regulator in tumor-associated macrophage polarization. J Microsc Ultrastruct. 2019; 7(2): 53-56.

[38] Ren M, Guo Y, Wei X, et al. TREM2 overexpression attenuates neuroinflammation and protects dopaminergic neurons in experimental models of Parkinson’s disease. Exp Neurol. 2018; 302: 205-213.

[39] Zhang J, Liu Y, Zheng Y, et al. TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus. J Neuroinflam. 2020; 17(1): 2.

[40] Brazil JC, Quiros M, Nusrat A, Parkos CA. Innate immune cell-epithelial crosstalk during wound repair. J Clin Invest. 2019; 129(8): 2983-2993.

[41] Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I. Diabetic wound-healing science. Medicina (Kaunas). 2021; 57(10): 1072.

[42] Zou Y, Takano H, Mizukami M, et al. Leukemia inhibitory factor enhances survival of cardiomyocytes and induces regeneration of myocardium after myocardial infarction. Circulation. 2003; 108(6): 748-753.

[43] Wang F, Trial J, Diwan A, et al. Regulation of cardiac fibroblast cellular function by leukemia inhibitory factor. J Mol Cell Cardiol. 2002; 34(10): 1309-1316.

[44] Thatcher JD. The inositol trisphosphate (IP3) signal transduction pathway. Sci Signal. 2010; 3(119): tr3.

[45] Maschalidi S, Mehrotra P, Keçeli BN, et al. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. Nature. 2022; 606(7915): 776-784.

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.