Macrophage polarization in diabetic wound healing

Abstract

Impaired wound healing is one of the severe complications of diabetes. Macrophages have been shown to play a vital role in wound healing. In different wound environments, macrophages are classified into two phenotypes: classically activated macrophages and alternatively activated macrophages. Dysregulation of macrophage phenotypes leads to severely impaired wound healing in diabetes. Particularly, uncontrolled inflammation and abnormal macrophage phenotype are important reasons hindering the closure of diabetic wounds. This article reviews the functions of macrophages at various stages of wound healing, the relationship between macrophage phenotypic dysregulation and diabetic wound healing and the mechanism of macrophage polarization in diabetic wound healing. New therapeutic drugs targeting phagocyte polarization to promote the healing of diabetic wounds might provide a new strategy for treating chronic diabetic wound healing.

Keywords

Diabetic wounds / Macrophage polarization / Signaling pathways / Wound healing / Therapeutics

References

[1] Zhang H, Nie X, Shi X, Zhao J, Chen Y, Yao Q, et al. Regulatory mechanisms of the Wnt/β-catenin pathway in diabetic cutaneous ulcers. Front Pharmacol. 2018; 9: 1114. https://doi.org/10.3389/fphar.2018.01114.

[2] Rice JB, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NB. Burden of diabetic foot ulcers for medicare and private insurers. Diabetes Care. 2014; 37: 651-8.

[3] Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011; 13: e23. https://doi.org/10.1017/S1462399411001943.

[4] Barman PK, Koh TJ. Macrophage dysregulation and impaired skin wound healing in diabetes. Front Cell Dev Biol. 2020; 8: 528. https://doi.org/10.3389/fcell.2020.00528.

[5] Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877: 173090. https://doi.org/10.1016/j.ejphar.2020.173090.

[6] Louiselle AE, Niemiec SM, Zgheib C, Liechty KW. Macrophage polarization and diabetic wound healing. Transl Res. 2021; 236: 109-16.

[7] Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017; 79: 541-66.

[8] Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013; 229: 176-85.

[9] Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH. Macrophages in skin injury and repair. Immunobiology. 2011; 216: 753-62.

[10] Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010; 32: 593-604.

[11] Ferrante CJ, Leibovich SJ. Regulation of macrophage polarization and wound healing. Adv Wound Care (New Rochelle). 2012; 1: 10-6.

[12] Zhou D, Huang C, Lin Z, Zhan S Kong L, Fang C, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal. 2014; 26: 192-7.

[13] Li Q, Lu L, Li X, Lu S. Long non-coding RNA NKILA alleviates airway inflammation in asthmatic mice by promoting M2 macrophage polarization and inhibiting the NF-κB pathway. Biochem Biophys Res Commun. 2021; 571: 46-52.

[14] Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C, et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell Signal. 2014; 26: 192-7.

[15] Zhang J, Yang P, Liu D, Gao M, Wang J, Yu T, et al. Inhibiting hyper-O-GlcNAcylation of c-Myc accelerate diabetic wound healing by alleviating keratinocyte dysfunction. Burns Trauma. 2021; 9: tkab031. https://doi.org/10.1093/burnst/tkab031.

[16] Wu MY, Lu JH. Autophagy and macrophage functions: inflammatory response and phagocytosis. Cell. 2020;9. https://doi.org/10.3390/cells9010070.

[17] Ren H, Zhao F, Zhang Q, Huang X, Wang Z. Autophagy and skin wound healing. Burns Trauma. 2022; 10: tkac003. https://doi.org/10.1093/burnst/tkac003.

[18] Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011; 11: 723-37.

[19] Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001; 69: 513-21.

[20] Baum CL, Arpey CJ. Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al]. 2005; 31: 674-86 discussion 86.

[21] Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 2013; 8: e80908. https://doi.org/10.1371/journal.pone.0080908.

[22] Edwards JP, Zhang X, Frauwirth KA, Mosser DM. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol. 2006; 80: 1298-307.

[23] Miao M, Niu Y, Xie T, Yuan B, Qing C, Lu S. Diabetes-impaired wound healing and altered macrophage activation: a possible pathophysiologic correlation. Wound Repair Regen. 2012; 20: 203-13.

[24] Aytaç A, Demir C, Alagöz M. Docosahexaenoic acid improves diabetic wound healing in a rat model by restoring impaired plasticity of macrophage progenitor cells. Plast Reconstr Surg. 2021; 145: 942e-50. https://doi.org/10.1097/PRS.0000000000006739.

[25] Xu X, Gu S, Huang X, Ren J, Gu Y, Wei C, et al. The role of macrophages in the formation of hypertrophic scars and keloids. Burns Trauma. 2020; 8: tkaa006. https://doi.org/10.1093/burnst/tkaa006.

[26] Huang YY, Lin CW, Cheng NC, Cazzell SM, Chen HH, Huang KF, et al. Effect of a novel macrophage-regulating drug on wound healing in patients with diabetic foot ulcers: a randomized clinical trial. JAMA Netw Open. 2021; 4: e2122607. https://doi.org/10.1001/jamanetworkopen.2021.22607.

[27] Aval SF, Lotfi H, Sheervalilou R, Zarghami N. Tuning of major signaling networks (TGF-β, Wnt, Notch and hedgehog) by miRNAs in human stem cells commitment to different lineages: possible clinical application. Biomed Pharmacother. 2017; 91: 849-60.

[28] Suresh S, Irvine AE. The NOTCH signaling pathway in normal and malignant blood cell production. Journal of cell communication and signaling. 2015; 9: 5-13.

[29] Xu H, Zhu J, Smith S, Foldi J, Zhao B, Chung AY, et al. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat Immunol. 2012; 13: 642-50.

[30] Lin Y, Zhao JL, Zheng QJ, Jiang X, Tian J, Liang SQ, et al. Notch Signaling modulates macrophage polarization and phagocytosis through direct suppression of signal regulatory protein α expression. Front Immunol. 2018; 9: 1744. https://doi.org/10.3389/fimmu.2018.01744.

[31] Hu X, Chung AY, Wu I, Foldi J, Chen J, Ji JD, et al. Integrated regulation of toll-like receptor responses by Notch and interferon-gamma pathways. Immunity. 2008; 29: 691-703.

[32] Liu H, Wang J, Zhang M, Xuan Q, Wang Z, Lian X, et al. Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients. Breast Cancer Res Treat. 2017; 166: 95-107.

[33] Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8: 958-69.

[34] Kimball AS, Joshi AD, Boniakowski AE, Schaller M, Chung J, Allen R, et al. Notch regulates macrophage-mediated inflammation in diabetic wound healing. Front Immunol. 2017; 8: 635. https://doi.org/10.3389/fimmu.2017.00635.

[35] Kimball AS, Joshi A, Carson WFT, Boniakowski AE, Schaller M, Allen R, et al. The histone Methyltransferase MLL1 directs macrophage-mediated inflammation in wound healing and is altered in a murine model of obesity and type 2 diabetes. Diabetes. 2017; 66: 2459-71.

[36] Singh SB, Coffman CN, Carroll-Portillo A, Varga MG, Lin HC. Notch Signaling pathway is activated by Sulfate reducing bacteria. Front Cell Infect Microbiol. 2021; 11: 695299. https://doi.org/10.3389/fcimb.2021.695299.

[37] Bai X, Li J, Li L, Liu M, Liu Y, Cao M, et al. Extracellular vesicles from adipose tissue-derived stem cells affect Notch-miR148a-3p Axis to regulate polarization of macrophages and alleviate sepsis in mice. Front Immunol. 2020; 11: 1391. https://doi.org/10.3389/fimmu.2020.01391.

[38] Na J, Lee K, Na W, Shin JY, Lee MJ, Yune TY, et al. Histone H3K27 demethylase JMJD3 in cooperation with NF-κB regulates keratinocyte wound healing. J Invest Dermatol. 2016; 136: 847-58.

[39] Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009; 1: a001651. https://doi.org/10.1101/cshperspect.a001651.

[40] Babu M, Durga Devi T, Makinen P, Kaikkonen M, Lesch HP, Junttila S, et al. Differential promoter methylation of macrophage genes is associated with impaired vascular growth in ischemic muscles of Hyperlipidemic and type 2 diabetic mice: genome-wide promoter methylation study. Circ Res. 2015; 117: 289-99.

[41] Baker RG, Hayden MS, Ghosh S. NF-kappaB, inflammation, and metabolic disease. Cell Metab. 2011; 13: 11-22.

[42] Kang HJ, Kumar S, D’Elia A, Dash B, Nanda V, Hsia HC, et al. Self-assembled elastin-like polypeptide fusion protein coacervates as competitive inhibitors of advanced glycation end-products enhance diabetic wound healing. J Control Release. 2021; 333: 176-87.

[43] Dong MW, Li M, Chen J, Fu TT, Lin KZ, Ye GH, et al. Activation of α7nAChR Promotes Diabetic Wound Healing by Suppressing AGE-Induced TNF-α Production. Inflammation. 2016; 39: 687-99.

[44] Yang HL, Tsai YC, Korivi M, Chang CT, Hseu YC. Lucidone promotes the cutaneous wound healing process via activation of the PI(3)K/AKT, Wnt/β-catenin and NF-κB Signaling pathways. Biochim Biophys Acta Mol Cell Res. 2017; 1864: 151-68.

[45] Peng X, He F, Mao Y, Lin Y, Fang J, Chen Y, et al. miR-146a promotes M2 macrophage polarization and accelerates diabetic wound healing by inhibiting the TLR4/NF-κB axis. J Mol Endocrinol. 2022; 69: 315-27.

[46] Feng J, Dong C, Long Y, Mai L, Ren M, Li L, et al. Elevated Kallikrein-binding protein in diabetes impairs wound healing through inducing macrophage M1 polarization. Cell Commun Signal. 2019; 17: 60. https://doi.org/10.1186/s12964-019-0376-9.

[47] Hahn M, Bürckert JP, Luttenberger CA, Klebow S, Hess M, Al-Maarri M, et al. Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling. Leukemia. 2018; 32: 72-82.

[48] Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012; 485: 55-61.

[49] Sun K, Luo J, Guo J, Yao X, Jing X, Guo F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthr Cartil. 2020; 28: 400-9.

[50] Li Y, Sun R, Zou J, Ying Y, Luo Z. Dual roles of the AMP-activated protein kinase pathway in angiogenesis. Cell. 2019;8. https://doi.org/10.3390/cells8070752.

[51] Costa B, Dangate M, Vetro M, Donvito G, Gabrielli L, Amigoni L, et al. Synthetic sulfoglycolipids targeting the serine-threonine protein kinase Akt. Bioorg Med Chem. 2016; 24: 3396-405.

[52] Bandarage UK, Aronov AM, Cao J, Come JH, Cottrell KM, Davies RJ, et al. Discovery of a novel series of potent and selective Alkynylthiazole-derived PI3K γ inhibitors. ACS Med Chem Lett. 2021; 12: 129-35.

[53] Vijay K. Toll-like receptors in immunity and inflammatory diseases: past, present, and future. Int Immunopharmacol. 2018;59:391-412.

[54] Jere SW, Houreld NN, Abrahamse H. Role of the PI3K/AKT (mTOR and GSK3beta) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 2019; 50: 52-9.

[55] Wang J, Liu J, Wang Y, Lin M, Tian W, Zhou L, et al. High glucose induces alternative activation of macrophages via PI3K/Akt signaling pathway. J Recept Signal Transduct Res. 2017; 37: 409-15.

[56] Cen M, Hu P, Cai Z, Fang T, Zhang J, Lu M. TIEG1 deficiency confers enhanced myocardial protection in the infarcted heart by mediating the Pten/Akt signalling pathway. Int J Mol Med. 2017; 39: 569-78.

[57] Elkenani M, Nyamsuren G, Raju P, Liakath-Ali K, Hamdaoui A, Kata A, et al. Pelota regulates epidermal differentiation by modulating BMP and PI3K/AKT Signaling pathways. J Invest Dermatol. 2016; 136: 1664-71.

[58] Gao YL, Liu CS, Zhao R, Wang LL, Li SS, Liu M, et al. Effects of PI3K/Akt Pathway in Wound Healing Process of Mice Skin. Fayi xue za zhi. 2016; 32: 7-12.

[59] Yu T, Gao M, Yang P, Liu D, Wang D, Song F, et al. Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR-γ signaling during diabetic wound healing. J Cell Physiol. 2019; 234: 4217-31.

[60] Li K, Li Q. LINC00323 mediates the role of M1 macrophage polarization in diabetic nephropathy through PI3K/AKT signaling pathway. Hum Immunol. 2021; 82: 960-7.

[61] Yang HL, Tsai YC, Korivi M, Chang CT, Hseu YC. Lucidone Promotes the Cutaneous Wound Healing Process via Activation of thePI(3)K/AKT, Wnt/β-catenin and NF-κB Signaling Pathways. Biochim Biophys ActaMol Cell Res. 2017; 1864: 151-68.

[62] Liu W, Yu M, Xie D, Wang L, Ye C, Zhu Q, et al. Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Res Ther. 2020; 11: 259. https://doi.org/10.1186/s13287-020-01756-x.

[63] Amini-Nik S, Cambridge E, Yu W, Guo A, Whetstone H, Nadesan P, et al. β-Catenin-regulated myeloid cell adhesion and migration determine wound healing. J Clin Invest. 2014; 124: 2599-610.

[64] Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012; 149: 1192-205.

[65] Gonzalez-Mariscal I, Pozo-Morales M, Romero-Zerbo SY, Espinosa-Jimenez V, Escamilla-Sanchez A, Sanchez-Salido L, et al. Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage. Biomed Pharmacother. 2022; 145: 112361. https://doi.org/10.1016/j.biopha.2021.112361.

[66] Geng K, Ma X, Jiang Z, Gu J, Huang W, Wang W, et al. WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice. Cell Biol Toxicol. 2022. https://doi.org/10.1007/s10565-022-09748-8.

[67] Li S, Ding X, Zhang H, Ding Y, Tan Q. IL-25 improves diabetic wound healing through stimulating M2 macrophage polarization and fibroblast activation. Int Immunopharmacol. 2022; 106: 108605. https://doi.org/10.1016/j.intimp.2022.108605.

[68] Yang Y, Huang Y, Zeng Z. Advances in cGAS-STING Signaling pathway and diseases. Front Cell Dev Biol. 2022; 10: 800393. https://doi.org/10.3389/fcell.2022.800393.

[69] Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021; 21: 548-69.

[70] Yuan L, Mao Y, Luo W, Wu W, Xu H, Wang XL, et al. Palmitic acid dysregulates the hippo-YAP pathway and inhibits angiogenesis by inducing mitochondrial damage and activating the cytosolic DNA sensor cGAS-STING-IRF3 signaling mechanism. J Biol Chem. 2017; 292: 15002-15.

[71] Ou L, Zhang A, Cheng Y, Chen Y. The cGAS-STING pathway: a promising immunotherapy target. Front Immunol. 2021; 12: 795048. https://doi.org/10.3389/fimmu.2021.795048.

[72] Das A, Datta S, Roche E, Chaffee S, Jose E, Shi L, et al. Novel mechanisms of collagenase Santyl ointment (CSO) in wound macrophage polarization and resolution of wound inflammation. Sci Rep. 2018; 8: 1696. https://doi.org/10.1038/s41598-018-19879-w.

[73] Paige JT, Kremer M, Landry J, Hatfield SA, Wathieu D, Brug A, et al. Modulation of inflammation in wounds of diabetic patients treated with porcine urinary bladder matrix. Regen Med. 2019; 14: 269-77.

[74] Fu J, Huang J, Lin M, Xie T, You T. Quercetin promotes diabetic wound healing via switching macrophages from M1 to M2 polarization. J Surg Res. 2020; 246: 213-23.

[75] Jia YC, Qiu S, Xu J, Kang QL, Chai YM. Docosahexaenoic acid improves diabetic wound healing in a rat model by restoring impaired plasticity of macrophage progenitor cells. Plast Reconstr Surg. 2020; 145: 942e-50.

[76] Lin CW, Chen CC, Huang WY, Chen YY, Chen ST, Chou HW, et al. Restoring Prohealing/Remodeling-associated M2a/c macrophages using ON101 accelerates diabetic wound healing. JID innovations: skin science from molecules to population health. 2022; 2: 100138. https://doi.org/10.1016/j.xjidi.2022.100138.

[77] Ngo TB, Spearman BS, Hlavac N, Schmidt CE. Three-dimensional bioprinted hyaluronic acid hydrogel test beds for assessing neural cell responses to competitive growth stimuli. ACS Biomater Sci Eng. 2020; 6: 6819-30.

[78] Montanaro M, Meloni M, Anemona L, Giurato L, Scimeca M, Izzo V, et al. Macrophage activation and M2 polarization in wound bed of diabetic patients treated by dermal/epidermal substitute Nevelia. Int J Low Extrem Wounds. 2022; 21: 377-83. https://doi.org/10.1177/1534734620945559.

[79] Wu J, Chen A, Zhou Y, Zheng S, Yang Y, An Y, et al. Novel H(2)S-releasing hydrogel for wound repair via in situ polarization of M2 macrophages. Biomaterials. 2019; 222: 119398. https://doi.org/10.1016/j.biomaterials.2019.119398.

[80] Gan J, Liu C, Li H, Wang S, Wang Z, Kang Z, et al. Accelerated wound healing in diabetes by reprogramming the macrophages with particle-induced clustering of the mannose receptors. Biomaterials. 2019; 219: 119340. https://doi.org/10.1016/j.biomaterials.2019.119340.

[81] Lu YF, Deng J, Wang J, Luo GX. Effects and mechanism of Lactococcus lactis thermo-sensitive hydrogel on the wound healing of full-thickness skin defects in diabetic mice. Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns. 2020; 36: 1117-29.

[82] Deng H, Chen Y. The role of adipose-derived stem cells-derived extracellular vesicles in the treatment of diabetic foot ulcer: trends and prospects. Front Endocrinol (Lausanne). 2022; 13: 902130. https://doi.org/10.3389/fendo.2022.902130.

[83] De Gregorio C, Contador D, Díaz D, Cárcamo C, Santapau D, Lobos-Gonzalez L, et al. Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice. Stem Cell Res Ther. 2020; 11: 168. https://doi.org/10.1186/s13287-020-01680-0.

[84] Willer H, Spohn G, Morgenroth K, Thielemann C, Elvers-Hornung S, Bugert P, et al. Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages. Front Immunol. 2022; 13: 976511. https://doi.org/10.3389/fimmu.2022.976511.

[85] Di G, Du X, Qi X, Zhao X, Duan H, Li S, et al. Mesenchymal stem cells promote diabetic corneal epithelial wound healing through TSG-6-dependent stem cell activation and macrophage switch. Invest Ophthalmol Vis Sci. 2017; 58: 4344-54.

[86] Sun Y, Song L, Zhang Y, Wang H, Dong X. Adipose stem cells from type 2 diabetic mice exhibit therapeutic potential in wound healing. Stem Cell Res Ther. 2020; 11: 298. https://doi.org/10.1186/s13287-020-01817-1.

[87] Self-Fordham JB, Naqvi AR, Uttamani JR, Kulkarni V, Nares S. MicroRNA: dynamic regulators of macrophage polarization and plasticity. Front Immunol. 2017; 8: 1062. https://doi.org/10.3389/fimmu.2017.01062.

[88] Du J, Li Q, Shen L, Lei H, Luo J, Liu Y, et al. miR-145a-5p promotes myoblast differentiation. Biomed Res Int. 2016; 2016: 5276271. https://doi.org/10.1155/2016/5276271.

[89] Hu J, Zhang L, Liechty C, Zgheib C, Hodges MM, Liechty KW, et al. Long noncoding RNA GAS5 regulates macrophage polarization and diabetic wound healing. J Invest Dermatol. 2020; 140: 1629-38.

[90] Yang P, Wang X, Wang D, Shi Y, Zhang M, Yu T, et al. Topical insulin application accelerates diabetic wound healing by promoting anti-inflammatory macrophage polarization. J Cell Sci. 2020; 133. https://doi.org/10.1242/jcs.235838.

[91] Wei P, Zhong C, Yang X, Shu F, Xiao S, Gong T, et al. Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function. Burns Trauma. 2020; 8: tkaa020. https://doi.org/10.1093/burnst/tkaa020.

[92] Hao Y, Yang L, Liu Y, Ye Y, Wang J, Yu C, et al. Mmu-miR-145a-5p accelerates diabetic wound healing by promoting macrophage polarization toward the M2 phenotype. Front Med (Lausanne). 2021; 8. https://doi.org/10.3389/fmed.2021.775523.

[93] Pi L, Fang B, Meng X, Qian L. LncRNA XIST accelerates burn wound healing by promoting M2 macrophage polarization through targeting IL-33 via miR-19b. Cell Death Dis. 2022; 8: 220. https://doi.org/10.1038/s41420-022-00990-x.