WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice

Kang Geng^#^{1

2

3}, Xiumei Ma^#^{1

2}, Zongzhe Jiang², Junling Gu⁴, Wei Huang², Weiming Wang^{1

5}, Yong Xu^{6

7}, Youhua Xu⁸

Affiliations

¹ Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao.
² Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China.
³ Department of Plastic and Burn Surgery, National Key Clinical Construction Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
⁴ Endocrinology Department, The Second People's Hospital of Yibin, West China Yibin Hospital, Sichuan University, Yibin, Sichuan, People's Republic of China.
⁵ Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
⁶ Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao. xywyll@swmu.edu.cn.
⁷ Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China. xywyll@swmu.edu.cn.
⁸ Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao. yhxu@must.edu.mo.

^# Contributed equally.

PMID: 35982296
DOI: 10.1007/s10565-022-09748-8

WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice

Kang Geng et al. Cell Biol Toxicol. 2023 Aug.

. 2023 Aug;39(4):1577-1591.

doi: 10.1007/s10565-022-09748-8. Epub 2022 Aug 19.

Authors

Kang Geng^#^{1

2

3}, Xiumei Ma^#^{1

2}, Zongzhe Jiang², Junling Gu⁴, Wei Huang², Weiming Wang^{1

5}, Yong Xu^{6

7}, Youhua Xu⁸

Affiliations

¹ Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao.
² Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China.
³ Department of Plastic and Burn Surgery, National Key Clinical Construction Specialty, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
⁴ Endocrinology Department, The Second People's Hospital of Yibin, West China Yibin Hospital, Sichuan University, Yibin, Sichuan, People's Republic of China.
⁵ Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
⁶ Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao. xywyll@swmu.edu.cn.
⁷ Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, People's Republic of China. xywyll@swmu.edu.cn.
⁸ Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao. yhxu@must.edu.mo.

^# Contributed equally.

PMID: 35982296
DOI: 10.1007/s10565-022-09748-8

Abstract

Diabetic foot ulcer (DFU) is a devastating component of diabetes progression, leading to decreased quality of life and increased mortality in diabetic patients. The underlying mechanism of DFU is not completely understood. Hence, this study aims to elucidate the mechanism involved in wound healing in mouse models of DFU. Gain- and loss-of-function studies were performed to study the roles that WDR74 and TGF-β play in mouse models of DFU and primary bone marrow-derived mouse macrophages. M1 and M2 macrophage phenotypic markers, extracellular matrix (ECM) components, and angiogenic makers were determined by RT-qPCR and/or Western blot analysis. Localization of these proteins was determined by immunofluorescence staining and/or immunohistochemistry. Interaction between WDR74 with Smad2/3 in macrophages was detected by co-immunoprecipitation. We found that WDR74 and M2 macrophages were decreased in wound tissues from DFU mice. TGF-β/Smad pathway activation increased the expression of M2 macrophage markers (arginase-1 and YM1), IL-4, while decreased expression of M1 macrophage marker (iNOS). TGF-β/Smad pathway activation also increased the production of ECM and promoted the wound closure in diabetic mice. We also noticed that WDR74 overexpression increased Smad2/3 phosphorylation, elevated the population of M2 macrophage and ECM production, and alleviated DFU. LY2109761 treatment normalized effects of TGF-β or WDR74 overexpression. In conclusion, WDR74 promoted M2 macrophage polarization, leading to improved DFU in mice, through activation of the TGF-β/Smad pathway. Graphical Headlights 1. WDR74 promotes M2 macrophage polarization and ECM production. 2. WDR74 activates the TGF-β/Smad signaling pathway. 3. TGF-β/Smad activation promotes M2 macrophage polarization in murine DFU. 4. WDR74 enhances wound healing in murine DFU.

Keywords: Diabetic foot ulcer, M2 macrophages; Fibroblasts; Smad; TGF-β; WDR74.

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References

1. Aambo A, Klemsdal TO. Cardiovascular disease and diabetes in patients with African or Asian background. Tidsskr Nor Laegeforen. 2017;137(22)
1. Akhurst RJ, Derynck R. TGF-beta signaling in cancer–a double-edged sword. Trends Cell Biol. 2001;11(11):S44-51. - PubMed - DOI
1. Al-Mulla F, Leibovich SJ, Francis IM, Bitar MS. Impaired TGF-beta signaling and a defect in resolution of inflammation contribute to delayed wound healing in a female rat model of type 2 diabetes. Mol Biosyst. 2011;7(11):3006–20. - PubMed - DOI
1. Awad F, Assrawi E, Jumeau C, Georgin-Lavialle S, Cobret L, Duquesnoy P, et al. Impact of human monocyte and macrophage polarization on NLR expression and NLRP3 inflammasome activation. PLoS One. 2017;12(4):e0175336. - PubMed - PMC - DOI
1. Costa Franco MM, Marim F, Guimaraes ES, Assis NRG, Cerqueira DM, Alves-Silva J, et al. Brucella abortus triggers a cGAS-independent STING pathway to induce host protection that involves guanylate-binding proteins and inflammasome activation. J Immunol. 2018;200(2):607–22. - PubMed - DOI

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WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice

Affiliations

WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice

Authors

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Abstract

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Medical

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