巨噬细胞在瘢痕疙瘩发病机制及治疗中的研究进展

doi:10.35541/cjd.20240090

Abstract

Abstract: 【Abstract】 Keloid is an abnormal fibroproliferative skin disease characterized by high recurrence rates and lack of clinically effective treatments. Currently, the pathogenesis of keloids is not yet clear, but accumulated evidence has indicated that macrophages play important roles in the progression of keloids. This review summarizes the polarization, mechanisms of action, and cellular crosstalk of macrophages in the pathogenesis of keloids, as well as macrophage-targeted therapies for keloids, aiming to provide new insights for the research and treatment of keloids.

Key words: Keloid, Macrophages, Transforming growth factor beta, Polarization, Extracellular matrix

Zhao Ying, Yang Yong, Wang Yan, Wei Qin, Wang Yetao. Role of macrophages in the pathogenesis and treatment of keloids[J]. Chinese Journal of Dermatology,2024,e20240090. doi:10.35541/cjd.20240090

References ［45］

［1］	Naik PP. Novel targets and therapies for keloid［J］. Clin Exp Dermatol, 2022,47（3）:507⁃515. doi: 10.1111/ced.14920.
［2］	Jin Q, Gui L, Niu F, et al. Macrophages in keloid are potent at promoting the differentiation and function of regulatory T cells［J］. Exp Cell Res,2018,362（2）:472⁃476. doi:10.1016/j.yexcr. 2017.12.011.
［3］	Bagabir R, Byers RJ, Chaudhry IH, et al. Site⁃specific immunophenotyping of keloid disease demonstrates immune upregulation and the presence of lymphoid aggregates［J］. Br J Dermatol, 2012,167（5）:1053⁃1066. doi: 10.1111/j.1365⁃2133. 2012.11190.x.
［4］	Shan X, Hu P, Ni L, et al. Serine metabolism orchestrates macrophage polarization by regulating the IGF1⁃p38 axis［J］. Cell Mol Immunol,2022,19（11）:1263⁃1278. doi:10.1038/s41423⁃022⁃00925⁃7.
［5］	Xia T, Fu S, Yang R, et al. Advances in the study of macrophage polarization in inflammatory immune skin diseases［J］. J Inflamm （Lond）, 2023,20（1）:33. doi: 10.1186/s12950⁃023⁃00360⁃z.
［6］	Lv W, Wu M, Ren Y, et al. Treatment of keloids through Runx2 siRNA‑induced inhibition of the PI3K/AKT signaling pathway［J］. Mol Med Rep, 2021,23（1）:55 ［pii］. doi: 10.3892/mmr. 2020.11693.
［7］	Wang X, Hu Z. tRNA derived fragment tsRNA⁃14783 promotes M2 polarization of macrophages in keloid［J］. Biochem Biophys Res Commun, 2022,636（Pt 2）:119⁃127. doi: 10.1016/j.bbrc. 2022.10.076.
［8］	Li X, Wang Y, Yuan B, et al. Status of M1 and M2 type macrophages in keloid［J］. Int J Clin Exp Pathol, 2017,10（11）:11098⁃11105.
［9］	Lv X, He Z, Yang M, et al. Analysis of subsets and localization of macrophages in skin lesions and peripheral blood of patients with keloids［J］. Heliyon, 2024,10（1）:e24034. doi: 10.1016/j.heliyon.2024.e24034.
［10］	Xie L, Law B K, Chytil A M, et al. Activation of the ERK pathway is required for TGF⁃beta1⁃induced EMT in vitro［J］. Neoplasia,2004,6（5）:603⁃610. doi:10.1593/neo.04241.
［11］	Peng D, Fu M, Wang M, et al. Targeting TGF⁃β signal transduction for fibrosis and cancer therapy［J］. Mol Cancer, 2022,21（1）:104. doi: 10.1186/s12943⁃022⁃01569⁃x.
［12］	Xu F, Liu C, Zhou D, et al. TGF⁃β/SMAD pathway and its regulation in hepatic fibrosis［J］. J Histochem Cytochem, 2016,64（3）:157⁃167. doi: 10.1369/0022155415627681.
［13］	Kuratomi G, Komuro A, Goto K, et al. NEDD4⁃2 （neural precursor cell expressed, developmentally down⁃regulated 4⁃2） negatively regulates TGF⁃beta （transforming growth factor⁃beta） signalling by inducing ubiquitin⁃mediated degradation of Smad2 and TGF⁃beta type I receptor［J］. Biochem J, 2005,386（Pt 3）:461⁃470. doi:10.1042/BJ20040738.
［14］	黄文华, 郑振龙, 金哲虎. 转化生长因子β/Smad信号通路及相关影响因子在瘢痕疙瘩中的研究进展［J］. 中华皮肤科杂志, 2023,56:E160⁃E164. doi: 10.35541/cjd.20220556.
［15］	Frangogiannis N. Transforming growth factor⁃β in tissue fibrosis［J］. J Exp Med, 2020,217（3）:e20190103. doi: 10.1084/jem. 20190103.
［16］	Li S, Zhang M, Long X, et al. Relative perfusion index: an objective, quantitative and noninvasive method for evaluating the severity of keloids［J］. Lasers Surg Med, 2022,54（8）:1071⁃1081. doi: 10.1002/lsm.23579.
［17］	Mironov AA, Mironov A, Sanavio B, et al. Intracellular membrane transport in vascular endothelial cells［J］. Int J Mol Sci, 2023,24（6）:5791. doi: 10.3390/ijms24065791.
［18］	Saati⁃Zarei A, Damirchi A, Tousi S, et al. Myocardial angiogenesis induced by concurrent vitamin D supplementation and aerobic⁃resistance training is mediated by inhibiting miRNA⁃15a, and miRNA⁃146a and upregulating VEGF/PI3K/eNOS signaling pathway［J］. Pflugers Arch, 2023,475（4）:541⁃555. doi: 10.1007/s00424⁃023⁃02788⁃x.
［19］	Lucas T, Waisman A, Ranjan R, et al. Differential roles of macrophages in diverse phases of skin repair［J］. J Immunol, 2010,184（7）:3964⁃3977. doi: 10.4049/jimmunol.0903356.
［20］	Liu J, Yang C, Zhang H, et al. Quantitative proteomics approach reveals novel biomarkers and pathological mechanism of keloid［J］. Proteomics Clin Appl, 2022,16（4）:e2100127. doi: 10.1002/prca.202100127.
［21］	张思敏，亓发芝. 巨噬细胞极化在增生性瘢痕和瘢痕疙瘩中的作用［J］. 中国免疫学杂志, 2019,35（5）:639⁃642.
［22］	Song J, Xu H, Lu Q, et al. Madecassoside suppresses migration of fibroblasts from keloids: involvement of p38 kinase and PI3K signaling pathways［J］. Burns, 2012,38（5）:677⁃684. doi: 10. 1016/j.burns.2011.12.017.
［23］	Peredo AP, Tsinman TK, Bonnevie ED, et al. Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus⁃like cell phenotype［J］. JOR Spine, 2024,7（1）:e1313. doi: 10.1002/jsp2.1313.
［24］	Guo C, Liang L, Zheng J, et al. UCHL1 aggravates skin fibrosis through an IGF⁃1⁃induced Akt/mTOR/HIF⁃1α pathway in keloid［J］. FASEB J, 2023,37（7）:e23015. doi: 10.1096/fj.202300153RR.
［25］	Xin Y, Min P, Xu H, et al. CD26 upregulates proliferation and invasion in keloid fibroblasts through an IGF⁃1⁃induced PI3K/AKT/mTOR pathway［J］. Burns Trauma, 2020,8:tkaa025. doi: 10.1093/burnst/tkaa025.
［26］	Phan P, Sonnaila S, Ternier G, et al. Overexpression and purification of mitogenic and metabolic fibroblast growth factors［J］. Methods Mol Biol, 2024,2762:151⁃181. doi: 10.1007/978⁃1⁃0716⁃3666⁃4_10.
［27］	Kuang L, Zhang C, Li B, et al. Human keratinocyte⁃derived exosomal MALAT1 promotes diabetic wound healing by upregulating MFGE8 via microRNA⁃1914⁃3p［J］. Int J Nanomedicine, 2023,18:949⁃970. doi: 10.2147/IJN.S399785.
［28］	da Cunha Colombo Tiveron LR, da Silva IR, da Silva MV, et al. High in situ mRNA levels of IL⁃22, TFG⁃β, and ARG⁃1 in keloid scars［J］. Immunobiology, 2018,223（12）:812⁃817. doi: 10.1016/j.imbio.2018.08.010.
［29］	Di X, Chen J, Li Y, et al. Crosstalk between fibroblasts and immunocytes in fibrosis: from molecular mechanisms to clinical trials［J］. Clin Transl Med, 2024,14（1）:e1545. doi: 10.1002/ctm2.1545.
［30］	Feng C, Shan M, Xia Y, et al. Single⁃cell RNA sequencing reveals distinct immunology profiles in human keloid［J］. Front Immunol, 2022,13:940645. doi: 10.3389/fimmu.2022.940645.
［31］	Parfejevs V, Debbache J, Shakhova O, et al. Injury⁃activated glial cells promote wound healing of the adult skin in mice［J］. Nat Commun, 2018,9（1）:236. doi: 10.1038/s41467⁃017⁃01488⁃2.
［32］	Direder M, Weiss T, Copic D, et al. Schwann cells contribute to keloid formation［J］. Matrix Biol, 2022,108:55⁃76. doi: 10.1016/j.matbio.2022.03.001.
［33］	Gong T, Wang Y, Dong S, et al. Single⁃cell RNA⁃seq reveals the communications between extracellular matrix⁃related components and Schwann cells contributing to the earlobe keloid formation［J］. Front Med （Lausanne）, 2022,9:1000324. doi: 10. 3389/fmed.2022.1000324.
［34］	Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg⁃mediated T cell suppression［J］. Front Immunol, 2012,3:51. doi: 10.3389/fimmu.2012.00051.
［35］	吕建平, 付文华, 王少华. VEGF及其受体与瘢痕疙瘩的研究进展［J］. 中国美容医学, 2007,16（8）:1151⁃1154. doi: 10.3969/j.issn.1008⁃6455.2007.08.055.
［36］	尚念胜, 牛燕英. A型肉毒毒素对瘢痕疙瘩成纤维细胞TGF⁃β/Smad通路和ERK通路表达的影响［J］. 中国美容医学, 2020,29（5）:104⁃109.
［37］	王金, 黄立军, 蒋宗英, 等. A型肉毒素对兔耳增生性瘢痕的抑制作用及机制［J］. 中国皮肤性病学杂志, 2023,37（4）:390⁃398. doi: 10.13735/j.cjdv.1001⁃7089.202202091.
［38］	Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients［J］. J Clin Invest, 2015,125（7）:2795⁃2807. doi: 10.1172/JCI77958.
［39］	Ding J, Ma Z, Liu H, et al. The therapeutic potential of a C⁃X⁃C chemokine receptor type 4 （CXCR⁃4） antagonist on hypertrophic scarring in vivo［J］. Wound Repair Regen, 2014,22（5）:622⁃630. doi: 10.1111/wrr.12208.
［40］	胡小桃, 李薇. 苦参碱联合氢化可的松对瘢痕疙瘩成纤维细胞的影响［J］. 中国临床药理学杂志, 2020,36（14）:2107⁃2110. doi: 10.13699/j.cnki.1001⁃6821.2020.14.055.
［41］	Hietanen KE, Järvinen TA, Huhtala H, et al. Treatment of keloid scars with intralesional triamcinolone and 5⁃fluorouracil injections ⁃ a randomized controlled trial［J］. J Plast Reconstr Aesthet Surg, 2019,72（1）:4⁃11. doi: 10.1016/j.bjps.2018.05.052.
［42］	Hao Y, Dong X, Zhang M, et al. Effects of hyperbaric oxygen therapy on the expression levels of the inflammatory factors interleukin⁃12p40, macrophage inflammatory protein⁃1β, platelet⁃derived growth factor⁃BB, and interleukin⁃1 receptor antagonist in keloids［J］. Medicine （Baltimore）, 2020,99（16）:e19857. doi: 10.1097/MD.0000000000019857.
［43］	Tang B, Zhu B, Liang Y, et al. Asiaticoside suppresses collagen expression and TGF⁃β/Smad signaling through inducing Smad7 and inhibiting TGF⁃βRI and TGF⁃βRII in keloid fibroblasts［J］. Arch Dermatol Res, 2011,303（8）:563⁃572. doi: 10.1007/s00403⁃010⁃1114⁃8.
［44］	Li DK, Wang GH. Asiaticoside reverses M2 phenotype macrophage polarization⁃evoked osteosarcoma cell malignant behaviour by TRAF6/NF⁃κB inhibition［J］. Pharm Biol, 2022,60（1）:1635⁃1645. doi: 10.1080/13880209.2022.2109688.
［45］	He L, Jhong JH, Chen Q, et al. Global characterization of macrophage polarization mechanisms and identification of M2⁃type polarization inhibitors［J］. Cell Rep, 2021,37（5）:109955. doi: 10.1016/j.celrep.2021.109955.

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Role of macrophages in the pathogenesis and treatment of keloids

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