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Advances in Therapy
Published in: Advances in Therapy 11/2020

Open Access 01-11-2020 | Diabetic Foot | Review

Mast Cells in Diabetes and Diabetic Wound Healing

Authors: Jie Dong, Lihong Chen, Ying Zhang, Navin Jayaswal, Ikram Mezghani, Weijie Zhang, Aristidis Veves

Published in: Advances in Therapy | Issue 11/2020

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Abstract

Mast cells (MCs) are granulated, immune cells of the myeloid lineage that are present in connective tissues. Apart from their classical role in allergies, MCs also mediate various inflammatory responses due to the nature of their secretory products. They are involved in important physiological and pathophysiological responses related to inflammation, chronic wounds, and autoimmune diseases. There are also indications that MCs are associated with diabetes and its complications. MCs and MC-derived mediators participate in all wound healing stages and are involved in the pathogenesis of non-healing, chronic diabetic foot ulcers (DFUs). More specifically, recent work has shown increased degranulation of skin MCs in human diabetes and diabetic mice, which is associated with impaired wound healing. Furthermore, MC stabilization, either systemic or local at the skin level, improves wound healing in diabetic mice. Understanding the precise role of MCs in wound progression and healing processes can be of critical importance as it can lead to the development of new targeted therapies for diabetic foot ulceration, one of the most devastating complications of diabetes.
Literature
1.
2.
Crivellato E, Beltrami CA, Mallardi F, Ribatti D. Paul Ehrlich’s doctoral thesis: a milestone in the study of mast cells. Br J Haematol. 2003;123:19–21.PubMed
3.
Lyons DO, Pullen NA. Beyond IgE: alternative mast cell activation across different disease states. Int J Mol Sci. 2020;21:1498.PubMedCentral
4.
Maurer M, Taube C, Schröder NW, et al. Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions. J Allergy Clin Immunol. 2019;144:S19–30.PubMed
5.
Varricchi G, Marone G. Mast cells: fascinating but still elusive after 140 years from their discovery. Int J Mol Sci. 2020;21:464.
6.
Varricchi G, Rossi FW, Galdiero MR, et al. Physiological roles of mast cells: Collegium Internationale Allergologicum update 2019. Int Arch Allergy Immunol. 2019;179:247–61.PubMed
7.
Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34+, c-kit+, and expresses aminopeptidase N (CD13). Blood J Am Soc Hematol. 1999;94:2333–42.
8.
Dahlin JS, Hallgren J. Mast cell progenitors: origin, development and migration to tissues. Mol Immunol. 2015;63:9–17.PubMed
9.
Dvorak AM, Morgan ES. Diamine oxidase-gold enzyme-affinity ultrastructural demonstration that human gut mucosal mast cells secrete histamine by piecemeal degranulation in vivo. J Allergy Clin Immunol. 1997;99:812–20.PubMed
10.
Welle M. Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol. 1997;61:233–45.PubMed
11.
Bischoff S, Sellge G, Lorentz A, Sebald W, Raab R, Manns M. IL-4 enhances proliferation and mediator release in mature human mast cells. Proc Natl Acad Sci. 1999;96:8080–5.PubMed
12.
Huber M, Cato AC, Ainooson GK, et al. Regulation of the pleiotropic effects of tissue-resident mast cells. J Allergy Clin Immunol. 2019;144:S31–45.PubMed
13.
Dwyer DF, Barrett NA, Austen KF. Immunological Genome Project C: expression profiling of constitutive mast cells reveals a unique identity within the immune system. Nat Immunol. 2016;17:878–87.PubMedPubMedCentral
14.
15.
16.
17.
Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev. 2018;282:121–50.PubMedPubMedCentral
18.
Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8:205–17.PubMed
19.
20.
Dudeck A, Köberle M, Goldmann O, et al. Mast cells as protectors of health. J Allergy Clin Immunol. 2019;144:S4–18.PubMed
21.
Piliponsky AM, Acharya M, Shubin NJ. Mast cells in viral, bacterial, and fungal infection immunity. Int J Mol Sci. 2019;20:2851.PubMedCentral
22.
Zimmermann C, Troeltzsch D, Giménez-Rivera V, et al. Mast cells are critical for controlling the bacterial burden and the healing of infected wounds. Proc Natl Acad Sci. 2019;116:20500–4.PubMed
23.
Stassen M, Hartmann A-K, Delgado SJ, Dehmel S, Braun A. Mast cells within cellular networks. J Allergy Clin Immunol. 2019;144:S46–54.PubMed
24.
25.
Elieh A, Komi D, Wohrl S, Bielory L. Mast cell biology at molecular level: a comprehensive review. Clin Rev Allergy Immunol. 2020;58:342–65.
26.
Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464:1293–300.PubMedPubMedCentral
27.
Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nature Rev Endocrinol. 2009;5:219.
28.
Willcox A, Richardson S, Bone A, Foulis A, Morgan N. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009;155:173–81.PubMedPubMedCentral
29.
Shi MA, Shi GP. Different roles of mast cells in obesity and diabetes: lessons from experimental animals and humans. Front Immunol. 2012;3:7.PubMedPubMedCentral
30.
Martino L, Masini M, Bugliani M, et al. Mast cells infiltrate pancreatic islets in human type 1 diabetes. Diabetologia. 2015;58:2554–62.PubMed
31.
Svensson J, Eising S, Mortensen HB, et al. High levels of immunoglobulin E and a continuous increase in immunoglobulin G and immunoglobulin M by age in children with newly diagnosed type 1 diabetes. Hum Immunol. 2012;73:17–25.PubMed
32.
Geoffrey R, Jia S, Kwitek AE, et al. Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat. J Immunol. 2006;177:7275–86.PubMed
33.
Oka T, Kalesnikoff J, Starkl P, Tsai M, Galli SJ. Evidence questioning cromolyn’s effectiveness and selectivity as a ‘mast cell stabilizer’ in mice. Lab Investig J Tech Methods Pathol. 2012;92:1472–82.
34.
Carlos D, Yaochite JN, Rocha FA, et al. Mast cells control insulitis and increase Treg cells to confer protection against STZ-induced type 1 diabetes in mice. Eur J Immunol. 2015;45:2873–85.PubMed
35.
Gutierrez DA, Fu W, Schonefeldt S, et al. Type 1 diabetes in NOD mice unaffected by mast cell deficiency. Diabetes. 2014;63:3827–34.PubMed
36.
Betto E, Usuelli V, Mandelli A, et al. Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype. Clin Immunol. 2017;178:29–38.PubMed
37.
Hübner MP, Larson D, Torrero MN, et al. Anti-FcεR1 antibody injections activate basophils and mast cells and delay type 1 diabetes onset in NOD mice. Clin Immunol. 2011;141:205–17.PubMedPubMedCentral
38.
Valle A, Giamporcaro GM, Scavini M, et al. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes. 2013;62:2072–7.PubMedPubMedCentral
39.
Komi DEA, Shafaghat F, Christian M. Crosstalk between mast cells and adipocytes in physiologic and pathologic conditions. Clin Rev Allergy Immunol. 2020;2020:1–13.
40.
Oishi Y, Manabe I. Integrated regulation of the cellular metabolism and function of immune cells in adipose tissue. Clin Exp Pharmacol Physiol. 2016;43:294–303.PubMed
41.
Zatterale F, Longo M, Naderi J, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. 2020;10:1607.PubMedPubMedCentral
42.
Żelechowska P, Wiktorska M, Różalska S, et al. Leptin receptor is expressed by tissue mast cells. Immunol Res. 2018;66:557–66.PubMedPubMedCentral
43.
Divoux A, Moutel S, Poitou C, et al. Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metabol. 2012;97:E1677–85.
44.
Poglio S, De Toni-Costes F, Arnaud E, et al. Adipose tissue as a dedicated reservoir of functional mast cell progenitors. Stem Cells. 2010;28:2065–72.PubMed
45.
Liu J, Divoux A, Sun J, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. 2009;15:940–5.PubMedPubMedCentral
46.
Zhou Y, Yu X, Chen H, et al. Leptin deficiency shifts mast cells toward anti-inflammatory actions and protects mice from obesity and diabetes by polarizing M2 macrophages. Cell Metab. 2015;22:1045–58.PubMedPubMedCentral
47.
Zhang X, Wang X, Yin H, et al. Functional inactivation of mast cells enhances subcutaneous adipose tissue browning in mice. Cell Rep. 2019;28(792–803):e794.
48.
Yabut JM, Desjardins EM, Chan EJ, et al. Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance. Nature Commun. 2020;2020:11.
49.
Gutierrez DA, Muralidhar S, Feyerabend TB, Herzig S, Rodewald HR. Hematopoietic kit deficiency, rather than lack of mast cells, protects mice from obesity and insulin resistance. Cell Metab. 2015;21:678–91.PubMed
50.
Chmelař J, Chatzigeorgiou A, Chung K-J, et al. No role for mast cells in obesity-related metabolic dysregulation. Front Immunol. 2016;7:524.PubMedPubMedCentral
51.
Einwallner E, Kiefer FW, Di Caro G, et al. Mast cells are not associated with systemic insulin resistance. Eur J Clin Invest. 2016;46:911–9.PubMed
52.
Altintas MM, Nayer B, Walford EC, et al. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids Health Dis. 2012;11:21.PubMedPubMedCentral
53.
Hickey FB, Martin F. Role of the immune system in diabetic kidney disease. Curr Diab Rep. 2018;18:20.PubMed
54.
Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim Biophys Acta. 2012;1822:14–20.PubMed
55.
Yin DD, Luo JH, Zhao ZY, Liao YJ, Li Y. Tranilast prevents renal interstitial fibrosis by blocking mast cell infiltration in a rat model of diabetic kidney disease. Mol Med Rep. 2018;17:7356–64.PubMed
56.
de Morais RB, do Couto-Muniz VP, Costa EN, et al. Mast cell population in the development of diabetic nephropathy: effects of renin angiotensin system inhibition. Biomed Pharmacother. 2018;107:1115–8.PubMed
57.
Spinas E, Kritas S, Saggini A, et al. Role of mast cells in atherosclerosis: a classical inflammatory disease. London: SAGE; 2014.
58.
Uemura K, Kondo H, Ishii Y, et al. Mast cells play an important role in the pathogenesis of hyperglycemia-induced atrial fibrillation. J Cardiovasc Electrophysiol. 2016;27:981–9.PubMed
59.
Patella V, de Crescenzo G, Lamparter-Schummert B, De Rosa G, Adt M, Marone G. Increased cardiac mast cell density and mediator release in patients with dilated cardiomyopathy. Inflamm Res. 1997;46:31–2.PubMed
60.
Patella V, Marino I, Arbustini E, et al. Stem cell factor in mast cells and increased mast cell density in idiopathic and ischemic cardiomyopathy. Circulation. 1998;97:971–8.PubMed
61.
Huang ZG, Jin Q, Fan M, et al. Myocardial remodeling in diabetic cardiomyopathy associated with cardiac mast cell activation. PLoS One. 2013;8:e60827.PubMedPubMedCentral
62.
He A, Fang W, Zhao K, et al. Mast cell-deficiency protects mice from streptozotocin-induced diabetic cardiomyopathy. Transl Res. 2019;208:1–14.PubMedPubMedCentral
63.
Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–21.PubMed
64.
Wallace HA, Basehore BM, Zito PM. Wound healing phases. In: StatPearls Treasure Island (FL). 2020.
65.
Egozi EI, Ferreira AM, Burns AL, Gamelli RL, Dipietro LA. Mast cells modulate the inflammatory but not the proliferative response in healing wounds. Wound Repair Regenerat. 2003;11:46–54.
66.
Theoharides TC, Donelan JM, Papadopoulou N, Cao J, Kempuraj D, Conti P. Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol Sci. 2004;25:563–8.PubMed
67.
Weller K, Foitzik K, Paus R, Syska W, Maurer M. Mast cells are required for normal healing of skin wounds in mice. FASEB J. 2006;20:2366–8.PubMed
68.
Noli C, Miolo A. The mast cell in wound healing. Vet Dermatol. 2001;12:303–13.PubMed
69.
Antsiferova M, Martin C, Huber M, et al. Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis. J Immunol. 2013;191:6147–55.PubMed
70.
Sehra S, Serezani AP, Ocaña JA, Travers JB, Kaplan MH. Mast cells regulate epidermal barrier function and the development of allergic skin inflammation. J Investig Dermatol. 2016;136:1429–37.PubMed
71.
Shubin NJ, Glukhova VA, Clauson M, et al. Proteome analysis of mast cell releasates reveals a role for chymase in the regulation of coagulation factor XIIIA levels via proteolytic degradation. J Allergy Clin Immunol. 2017;139:323–34.PubMed
72.
Wulff BC, Parent AE, Meleski MA, DiPietro LA, Schrementi ME, Wilgus TA. Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol. 2012;132:458–65.PubMed
73.
Lamont P, Franklyn K, Rayman G, Boulton AJ. Update on the diabetic foot 2012: the 14th biennial Malvern Diabetic Foot Conference, May 9–11, 2012. Int J Lower Extremity Wounds. 2013;12:71–5.
74.
Den Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing. Transl Res. 2019;204:39–50.
75.
Dinh T, Tecilazich F, Kafanas A, et al. Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes. 2012;61:2937–47.PubMedPubMedCentral
76.
Tellechea A, Kafanas A, Leal EC, et al. Increased skin inflammation and blood vessel density in human and experimental diabetes. Int J Low Extrem Wounds. 2013;12:4–11.PubMedPubMedCentral
77.
Leal EC, Carvalho E, Tellechea A, et al. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am J Pathol. 2015;185:1638–48.PubMedPubMedCentral
78.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.PubMed
79.
80.
Sindrilaru A, Peters T, Wieschalka S, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Investig. 2011;121:985–97.PubMed
81.
82.
Theocharidis G, Bhasin S, Kounas K, Bhasin M, Veves A. Single cell RNA-seq analyses of healthy lower extremity skin and diabetic foot ulcers uncover distinct immune landscape of diabetic wound healing. Diabetes. 2018;67:647-P.
83.
84.
Strang H, Kaul A, Parikh U, et al. Chapter 11—role of cytokines and chemokines in wound healing. In: Bagchi D, Das A, Roy S, editors. Wound healing, tissue repair, and regeneration in diabetes. San Diego: Academic; 2020, p. 197–235.
85.
Bot I, Velden DV, Bouwman M, et al. Local mast cell activation promotes neovascularization. Cells. 2020;2020:9.
86.
Nazari M, Ni NC, Lüdke A, et al. Mast cells promote proliferation and migration and inhibit differentiation of mesenchymal stem cells through PDGF. J Mol Cell Cardiol. 2016;94:32–42.PubMed
87.
Dong X, Chen J, Zhang Y, Cen Y. Mast cell chymase promotes cell proliferation and expression of certain cytokines in a dose-dependent manner. Mol Med Rep. 2012;5:1487–90.PubMed
88.
Vangansewinkel T, Geurts N, Quanten K, et al. Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6. FASEB J. 2016;30:2040–57.PubMed
89.
Gimenez-Rivera V-A, Siebenhaar F, Zimmermann C, Siiskonen H, Metz M, Maurer M. Mast cells limit the exacerbation of chronic allergic contact dermatitis in response to repeated allergen exposure. J Immunol. 2016;197:4240–6.PubMed
90.
Balsam LB, DeAnda A Jr. The mast cell demystified: a novel target for anti-inflammatory strategies after circulatory arrest? J Thorac Cardiovasc Surg. 2017;153:77.PubMed
91.
de Souza Junior DA, Santana C, Vieira GV, Oliver C, Jamur MC. Mast cell protease 7 promotes angiogenesis by degradation of integrin subunits. cells. 2019;8:349.PubMedCentral
92.
Perez-Favila A, Martinez-Fierro ML, Rodriguez-Lazalde JG, et al. Current therapeutic strategies in diabetic foot ulcers. Medicina. 2019;55:714.PubMedCentral
93.
Gallant-Behm CL, Hildebrand KA, Hart DA. The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs. Wound Repair Regenerat. 2008;16:226–33.
94.
Chen L, Schrementi ME, Ranzer MJ, Wilgus TA, DiPietro LA. Blockade of mast cell activation reduces cutaneous scar formation. PLoS One. 2014;9:e85226.PubMedPubMedCentral
95.
Tellechea A, Bai S, Dangwal S, et al. Topical application of a mast cell stabilizer improves impaired diabetic wound healing. J Invest Dermatol. 2020;140(901–911):e911.
96.
Kouhkheil R, Fridoni M, Abdollhifar M-A, et al. Impact of photobiomodulation and condition medium on mast cell counts, degranulation, and wound strength in infected skin wound healing of diabetic rats. Photobiomodul Photomed Laser Surg. 2019;37:706–14.PubMed
97.
Babaei S, Ansarihadipour H, Nakhaei M, et al. Effect of Omegaven on mast cell concentration in diabetic wound healing. J Tissue Viabil. 2017;26:125–30.
98.
McLaughlin PJ, Cain JD, Titunick MB, Sassani JW, Zagon IS. Topical naltrexone is a safe and effective alternative to standard treatment of diabetic wounds. Adv Wound Care. 2017;6:279–88.
99.
Orenstein S, Saberski E, Klueh U, Kreutzer D, Novitsky Y. Effects of mast cell modulation on early host response to implanted synthetic meshes. Hernia. 2010;14:511–6.PubMed
Metadata
Title
Mast Cells in Diabetes and Diabetic Wound Healing
Authors
Jie Dong
Lihong Chen
Ying Zhang
Navin Jayaswal
Ikram Mezghani
Weijie Zhang
Aristidis Veves
Publication date
01-11-2020
Publisher
Springer Healthcare
Published in
Advances in Therapy / Issue 11/2020
Print ISSN: 0741-238X
Electronic ISSN: 1865-8652
DOI
https://doi.org/10.1007/s12325-020-01499-4

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