The role of macrophages in the formation of hypertrophic scars and keloids

Xiangwen Xu , Shuchen Gu , Xin Huang , Jieyi Ren , Yihui Gu , Chengjiang Wei , Xiang Lian , Haizhou Li , Yashan Gao , Rui Jin , Bin Gu , Tao Zan , Zhichao Wang

Burns & Trauma ›› 2020, Vol. 8 ›› Issue (1) : tkaa006

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Burns & Trauma ›› 2020, Vol. 8 ›› Issue (1) :tkaa006 DOI: 10.1093/burnst/tkaa006
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The role of macrophages in the formation of hypertrophic scars and keloids
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Abstract

Numerous studies have shown that macrophages can orchestrate the microenvironment from the early stage of wound healing to the later stages of scar formation. However, few reviews have highlighted the significance of macrophages during the formation of abnormal scars. The purpose of this review was to outline the polarization of macrophages from early to late stage of pathological scar formation, focusing on spatiotemporal diversity of M1 and M2 macrophages. In this review, the role of macrophages in the formation of hypertrophic scars and keloids is summarized in detail. First, an increased number of M2 cells observed before injuries are significantly associated with susceptibility to abnormal scar pathogenesis. Second, decreased expression of M1 at the early stage and delayed expression of M2 at the late stage results in pathological scar formation. Third, M2 cells are highly expressed at both the margin and the superficial region, which is consistent with the invasive property of keloids. Finally, this review helps to characterize strategies for the prediction and prevention of pathological scar formation.

Keywords

Hypertrophic scar / Keloid / Macrophages / Predisposition / Wound healing

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Xiangwen Xu, Shuchen Gu, Xin Huang, Jieyi Ren, Yihui Gu, Chengjiang Wei, Xiang Lian, Haizhou Li, Yashan Gao, Rui Jin, Bin Gu, Tao Zan, Zhichao Wang. The role of macrophages in the formation of hypertrophic scars and keloids. Burns & Trauma, 2020, 8 (1) : tkaa006 DOI:10.1093/burnst/tkaa006

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References

[1]

Gangemi EN, Gregori D, Berchialla P, Zingarelli E, Cairo M, Bollero D, et al. Epidemiology and risk factors for pathologic scarring after burn wounds. Arch Facial Plast Surg. 2008; 10: 93-102.

[2]

Finnerty CC, Jeschke MG, Branski LK, Barret JP, Dziewulski P, Herndon DN. Hypertrophic scarring: The greatest unmet challenge after burn injury. Lancet 2016; 388: 1427-1436.

[3]

Arno AI, Gauglitz GG, Barret JP, Jeschke MG. Up-to-date approach to manage keloids and hypertrophic scars: A useful guide. Burns 2014; 40: 1255-1266.

[4]

van der Veer WM, Bloemen MCT, Ulrich MMW, Molema G, van Zuijlen PP, Middelkoop E, et al. Potential cellular and molecular causes of hypertrophic scar formation. Burns 2009; 35: 15-29.

[5]

Trace AP, Enos CW, Mantel A, Keloids HVM. Hypertrophic scars: A Spectrum of clinical challenges. Am J Clin Dermatol. 2016; 17: 201-223.

[6]

Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Müller W, et al. Differential roles of macrophages in diverse phases of skin repair. 2010; 184: 3964-3977.

[7]

Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017; 18: 1-10.

[8]

Zhu Z, Ding J, Ma Z, Iwashina T, Tredget EE.Systemic depletion of macrophages in the subacute phase of wound healing reduces hypertrophic scar formation. Wound Repair Regen. 2016; 24: 644-656.

[9]

Mirza R, DiPietro LA, Koh TJ. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol. 2009; 175: 2454-2462.

[10]

Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nat Rev Immuno. 2017; 17: 349-362.

[11]

Vishwakarma A, Bhise NS, Evangelista MB, Rouwkema J, Dokmeci MR, Ghaemmaghami AM, et al. Engineering Immunomodulatory biomaterials to tune the inflammatory response. Trends Biotechnol. 2016; 34: 470-482.

[12]

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; 1: 1-22.

[13]

Baum CL, Arpey CJ. Normal cutaneous wound healing: Clinical correlation with cellular and molecular events. Dermatol Surg. 2005; 31: 674-686.

[14]

Limandjaja GC, Waaijman T, Roffel S, Niessen FB, Gibbs S. Monocytes co-cultured with reconstructed keloid and normal skin models skew towards M2 macrophage phenotype. Arch Dermatol Res 2019; 311: 615-627.

[15]

Martin P, Leibovich SJ. Inflammatory cells during wound repair: The good, the bad and the ugly. Trends Cell Biol 2005; 15: 599-607.

[16]

Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003; 83: 835-870.

[17]

Vogel DYS, Glim JE, Stavenuiter AWD, Breur M, Heijnen P, Amor S, et al. Human macrophage polarization in vitro: Maturation and activation methods compared. Immunobiology. 2014; 219: 695-703.

[18]

Boyette LB, Macedo C, Hadi K, Elinoff BD, Walters JT, Ramaswami B, et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One. 2017; 12: e0176460.

[19]

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: 2599-2610.

[20]

Sinha M, Sen CK, Singh K, Das A, Ghatak S, Rhea B, et al. Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue. Nat Commun. 2018; 9: 936.

[21]

Verreck FAW, de Boer T, Langenberg DML, van der Zanden L, Ottenhoff THM. Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma-and CD40L-mediated costimulation. J Leukoc Biol 2006; 79: 285-293.

[22]

Wilgus TA.Immune cells in the healing skin wound: Influential players at each stage of repair. Pharmacol Res. 2008; 58: 112-116.

[23]

Ogle ME, Segar CE, Sridhar S, Botchwey EA. Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design. Exp Biol Med. 2016; 241: 1084-1097.

[24]

Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8: 958-969.

[25]

Garash R, Bajpai A, Marcinkiewicz BM, Spiller KL. Drug delivery strategies to control macrophages for tissue repair and regeneration. Exp Biol Med (Maywood). 2016; 241: 1054-1063.

[26]

Ferrante CJ, Leibovich SJ. Regulation of macrophage polarization and wound healing. Adv Wound Care. 2012; 1: 10-16.

[27]

Sunakawa Y, Stintzing S, Cao S, Heinemann V, Cremolini C, Falcone A, et al. Variations in genes regulating tumor-associated macrophages (TAMs) to predict outcomes of bevacizumab-based treatment in patients with metastatic colorectal cancer: Results from TRIBE and FIRE3 trials. Ann Oncol. 2015; 26: 2450-2456.

[28]

Shaker SA, Ayuob NN, Hajrah NH. Cell talk: A phenomenon observed in the keloid scar by immunohistochemical study. Appl Immunohistochem Mol Morphol. 2011; 19: 153-159.

[29]

Bagabir R, Byers R, Chaudhry I, Müller W, Paus R, Bayat A. Site-specific immunophenotyping of keloid disease demonstrates immune upregulation and the presence of lymphoid aggregates. Br J Dermatol. 2012; 167: 1053-1066.

[30]

Novak ML, Koh TJ. Macrophage phenotypes during tissue repair. J Leukoc Biol 2013; 93: 875-811.

[31]

Lee S, Huen S, Nishio H, Nishio S, Lee HK, Choi B-S, et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol. 2011; 22: 317-326.

[32]

Tacke F, Zimmermann HW.Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014; 60: 1090-1096.

[33]

Jin Q, Gui L, Niu F, Yu B, Lauda N, Liu J, et al. Macrophages in keloid are potent at promoting the differentiation and function of regulatory T cells. Exp Cell Res. 2018; 362: 472-476.

[34]

Li X, Wang Y, Yuan B, Yang H, Qiao L. Status of M1 and M2 type macrophages in keloid. Int J Clin Exp Pathol. 2017; 10: 11098-11105.

[35]

Keloid OR. Hypertrophic scars are the result of chronic inflammation in the reticular dermis. Int J Mol Sci. 2017; 18: 1-10.

[36]

Shih B, Bayat A. Genetics of keloid scarring. Arch Dermatol Res. 2016; 25: 319-339.

[37]

Ii DAG. Current understanding of the genetic causes of Keloid formation. J Invest Dermatol. 2017; 18: S50-S53.

[38]

Butzelaar L, Schooneman DPM, Soykan EA, Talhout W, Ulrich MMW, van den Broek LJ, et al. Inhibited early immunologic response is associated with hypertrophic scarring. Exp Dermatol. 2016; 25: 797-804.

[39]

Rodero MP, Khosrotehrani K. Skin wound healing modulation by macrophages. Int J Clin Exp Pathol. 2010; 3: 643-653.

[40]

Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013; 14: 986-995.

[41]

Butzelaar L, Niessen FB, Talhout W, Schooneman DPM, Ulrich MM, Beelen RHJ, et al. Different properties of skin of different body sites: The root of keloid formation? Wound Repair Regen. 2017; 25: 758-766.

[42]

Delavary B, Glim J, Niessen F, Middelkoop E, van Egmond M, Beelen R. Macrophage phenotype and function in hypertrophic and normotrophic scars. Wound Repair Regen. 2011; 19: A85.

[43]

Prasai A, El Ayadi A, Jay J, Herndon DN, Finnerty CC. Changes in macrophage phenotype in hypertrophic scarring population. Wound Repair Regen. 2018; 26: A3.

[44]

Xie L, Yang Y, Meng J, Wen T, Liu J, Xu H. Cationic polysaccharide spermine-pullulan drives tumor associated macrophage towards M1 phenotype to inhibit tumor progression. Int J Biol Macromol 2019; 15: 1012-1019.

[45]

Ma S, Liu M, Xu Z, Li Y, Guo H, Ge Y, et al. A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression. Oncotarget. 2016; 7: 13502-13519.

[46]

Moore CS, Rao VTS, Durafourt BA, Bedell BJ, Ludwin SK. Bar-or a, et al. MiR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. Ann Neurol. 2013; 74: 709-720.

[47]

Lin L, Lin H, Wang L, Wang B, Hao X, Shi Y. MiR-130a regulates macrophage polarization and is associated with non-small cell lung cancer. Oncol Rep. 2015; 34: 3088-3096.

[48]

Gal P, Varinska L, Faber L, Novak S, Szabo P, Mitrengova P, et al. How Signaling molecules regulate tumor microenvironment: Parallels to wound repair. Molecules. 2017; 22: 1-17.

[49]

Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RHJ. Macrophages in skin injury and repair. Immunobiology. 2011; 216: 753-762.

[50]

Chen L, Wang J, Li S, Yu Z, Liu B, Song B, et al. The clinical dynamic changes of macrophage phenotype and function in different stages of human wound healing and hypertrophic scar formation. Int Wound J 2019; 16: 360-369.

[51]

Boyce DE, Ciampolini J, Ruge F, Murison MS, Harding KG. Inflammatory-cell subpopulations in keloid scars. Br J Plast Surg. 2001; 54: 511-516.

[52]

van den Broek LJ, van der Veer WM, de Jong EH, Gibbs S, Niessen FB. Suppressed inflammatory gene expression during human hypertrophic scar compared to normotrophic scar formation. Exp Dermatol. 2015; 24: 623-629

[53]

Liu H, Ding J, Ma Z, Zhu Z, Shankowsky HA, Tredget EE. A novel subpopulation of peripheral blood mononuclear cells presents in major burn patients. Burns 2015; 41: 988-1007.

[54]

Zhu Z, Ding J, Ma Z, Iwashina T, Tredget EE. The natural behavior of mononuclear phagocytes in HTS formation. Wound Repair Regen. 2016; 24: 14-25.

[55]

Ud-Din S, McGeorge D, Bayat A. Immune cell activity in human cutaneous wound healing and skin scarring: A multiple time point immunohistochemical study. Wound Repair Regen 2019; 27: A16.

[56]

Adeyemi-Doro HO. Keloids: The natural history. Afr J Med Med Sci. 1976; 5: 93-100.

[57]

Kose O, Waseem A. Keloids and hypertrophic scars: Are they two different sides of the same coin? Dermatol Surg. 2008; 34: 336-346.

[58]

Mari W, Alsabri SG, Tabal N, Younes S, Sherif A, Simman R. Novel insights on understanding of Keloid scar: Article review. J Am Coll Clin Wound Spec. 2015; 7: 1-7.

[59]

Jumper N, Hodgkinson T, Paus R, Bayat A. Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology. PloS one. 2017; 12: 1-33.

[60]

Syed F, Ahmadi E, Iqbal SA, Singh S, McGrouther DA, Bayat A. Fibroblasts from the growing margin of keloid scars produce higher levels of collagen i and III compared with intralesional and extralesional sites: Clinical implications for lesional site-directed therapy. Br J Dermatol. 2011; 164: 83-96.

[61]

Huang C, Akaishi S, Hyakusoku H, Ogawa R. Can the clinically separated hypertrophic scar and keloid be successive under the microscope?-a fibroproliferative skin disorder hypothesis. Wound Repair Regen. 2011; 19: A27.

[62]

Jiao H, Zhang T, Fan J, Xiao R. The superficial dermis may initiate keloid formation: Histological analysis of the keloid dermis at different depths. Front Physiol. 2017; 7: 1-9.

[63]

Bagabir R, Byers R, Chaudhry I, Muller W, Paus R, Bayat A. Site-specific immunophenotyping of keloid disease reveals the presence of keloid-associated lymphoid tissue (KALT). Wound Repair Regen. 2012; 20: 1053-1066.

[64]

Huang C, Akaishi S, Hyakusoku H, Ogawa R. Are keloid and hypertrophic scar different forms of the same disorder? A fibroproliferative skin disorder hypothesis based on keloid findings. Int Wound J. 2014; 11: 517-522.

[65]

Bux S, Madaree A. Keloids show regional distribution of proliferative and degenerate connective tissue elements. Cells Tissues Organs. 2010; 191: 213-234.

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