Shu-Mei Huang1, Ching-Shuang Wu2, Min-Hsi Chiu1, Chin-Han Wu1, Yu-Tang Chang3, Gwo-Shing Chen4, Cheng-Che E Lan5. 1. Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 2. Department of Medical Laboratory Science and Biotechnology, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. 3. Division of Pediatric Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. 4. Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address: d700086@kmu.edu.tw. 5. Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address: laneric@kmu.edu.tw.
Abstract
BACKGROUND: Macrophages play important roles during wound healing, and delayed healing in diabetics is associated with sustained inflammation. M1 type macrophage is recognized to secrete excessive amount of tumor necrosis factor-alpha (TNF-α) as compared to its M2 counterpart. OBJECTIVES: We hypothesized that macrophage polarization is different between diabetic and normal rats during skin wounding and has direct impact on keratinocyte function in the context of re-epithelialization. METHODS: Skin wounds were created in diabetic and control rats. The phenotypes of infiltrating macrophages, the levels of TNF-α, and the rate of wound closure were determined. Using cell model, the effects of M1 type macrophage on keratinocyte migration were evaluated, and the potential regulatory pathways were determined. RESULTS: The percentage of M1 macrophages and the levels of TNF-α expression were significantly higher in the perilesional area of diabetic rats as compared to control. The condition media (CM) from M1 type macrophage upregulated tissue inhibitor metalloproteinases (TIMP)-1 expression in keratinocytes and significantly reduced keratinocyte migratory capacity. Addition of neutralizing TNF-α antibody to the CM or gene-silencing of TIMP1 in keratinocytes restored the keratinocyte migratory capacity. Treating wounds of diabetic rats with TNF-α antagonist improved the wound healing process. CONCLUSIONS: In summary, high glucose wound environment harbored more M1 macrophages infiltration, an event that created excess TNF-α micro-environment. TNF-α upregulated TIMP1 expression in keratinocytes and resulted in impaired keratinocyte migration. Taken together, these events contributed to impaired wound healing during diabetic condition, and targeting TNF-α is a potential therapeutic option to improve diabetic wound healing.
BACKGROUND: Macrophages play important roles during wound healing, and delayed healing in diabetics is associated with sustained inflammation. M1 type macrophage is recognized to secrete excessive amount of tumor necrosis factor-alpha (TNF-α) as compared to its M2 counterpart. OBJECTIVES: We hypothesized that macrophage polarization is different between diabetic and normal rats during skin wounding and has direct impact on keratinocyte function in the context of re-epithelialization. METHODS: Skin wounds were created in diabetic and control rats. The phenotypes of infiltrating macrophages, the levels of TNF-α, and the rate of wound closure were determined. Using cell model, the effects of M1 type macrophage on keratinocyte migration were evaluated, and the potential regulatory pathways were determined. RESULTS: The percentage of M1 macrophages and the levels of TNF-α expression were significantly higher in the perilesional area of diabeticrats as compared to control. The condition media (CM) from M1 type macrophage upregulated tissue inhibitor metalloproteinases (TIMP)-1 expression in keratinocytes and significantly reduced keratinocyte migratory capacity. Addition of neutralizing TNF-α antibody to the CM or gene-silencing of TIMP1 in keratinocytes restored the keratinocyte migratory capacity. Treating wounds of diabeticrats with TNF-α antagonist improved the wound healing process. CONCLUSIONS: In summary, high glucose wound environment harbored more M1 macrophages infiltration, an event that created excess TNF-α micro-environment. TNF-α upregulated TIMP1 expression in keratinocytes and resulted in impaired keratinocyte migration. Taken together, these events contributed to impaired wound healing during diabetic condition, and targeting TNF-α is a potential therapeutic option to improve diabetic wound healing.
Authors: Maryam Sharifiaghdam; Elnaz Shaabani; Reza Faridi-Majidi; Stefaan C De Smedt; Kevin Braeckmans; Juan C Fraire Journal: Mol Ther Date: 2022-08-02 Impact factor: 12.910
Authors: Miriam E van Gent; Tanny J K van der Reijden; Patrick R Lennard; Adriëtte W de Visser; Bep Schonkeren-Ravensbergen; Natasja Dolezal; Robert A Cordfunke; Jan Wouter Drijfhout; Peter H Nibbering Journal: Antibiotics (Basel) Date: 2022-05-17
Authors: O A Krasilnikova; D S Baranovskii; A V Lyundup; P V Shegay; A D Kaprin; I D Klabukov Journal: Stem Cell Rev Rep Date: 2022-04-27 Impact factor: 6.692