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Tytuł:
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Lack of lymphocytes impairs macrophage polarization and angiogenesis in diabetic wound healing.
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Autorzy:
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Seraphim PM; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Department of Physiotherapy, School of Sciences and Technology, Sao Paulo State University - UNESP, Campus Presidente Prudente, Brazil.
Leal EC; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Instituto de Investigação Interdisciplinar, University of Coimbra, 3030-789 Coimbra, Portugal.
Moura J; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; INEB - Instituto Nacional de Engenharia Biomédica, University of Porto, Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
Gonçalves P; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Innate Immunity Unit, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France.
Gonçalves JP; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Cell Biology Department, Federal University of Paraná, Curitiba, PR, Brazil.
Carvalho E; Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal; Instituto de Investigação Interdisciplinar, University of Coimbra, 3030-789 Coimbra, Portugal; The Portuguese Diabetes Association (APDP), Lisbon, Portugal; Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA; Arkansas Children's Research Institute, Little Rock, AR 72202, USA. Electronic address: .
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Źródło:
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Life sciences [Life Sci] 2020 Aug 01; Vol. 254, pp. 117813. Date of Electronic Publication: 2020 May 16.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
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MeSH Terms:
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DNA-Binding Proteins/*physiology
Diabetes Mellitus, Experimental/*physiopathology
Interleukin Receptor Common gamma Subunit/*physiology
Lymphocytes/*physiology
Neovascularization, Physiologic/*physiology
Wound Healing/*physiology
Animals ; DNA-Binding Proteins/genetics ; Inflammation/metabolism ; Interleukin Receptor Common gamma Subunit/genetics ; Macrophage Activation/physiology ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Knockout ; Reactive Oxygen Species/metabolism ; Skin/blood supply ; Skin/metabolism
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Contributed Indexing:
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Keywords: Diabetes; Inflammation; Lymphocytes; Reactive oxygen species; Wound healing
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Substance Nomenclature:
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0 (DNA-Binding Proteins)
0 (Il2rg protein, mouse)
0 (Interleukin Receptor Common gamma Subunit)
0 (Rag2 protein, mouse)
0 (Reactive Oxygen Species)
EC 3.4.24.35 (Matrix Metalloproteinase 9)
EC 3.4.24.35 (Mmp9 protein, mouse)
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Entry Date(s):
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Date Created: 20200520 Date Completed: 20200629 Latest Revision: 20200629
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Update Code:
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20240105
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DOI:
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10.1016/j.lfs.2020.117813
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PMID:
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32428597
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Aims: This study aimed to investigate the effect of lymphocytes in wound healing and the underlying mechanisms, in diabetic and non-diabetic mice, using Balb/c recombination activating gene (Rag)-2 and interleukin 2 receptor gamma (IL-2Rγ) double knockout (KO) (RAG2 -/- IL-2Rγ -/- ) mice.
Main Methods: Wound healing in vivo was performed in control and STZ-induced diabetic mice, in both KO and WT mice. Inflammation and ROS production were evaluated by immunofluorescence microscopy analysis, antioxidant enzymes and angiogenesis were evaluated by quantitative PCR and immunofluorescence microscopy analysis, and wound closure kinetics evolution was evaluated by measurement of acetate tracing of the wound area.
Key Findings: Wound closure was significantly delayed in KO mice, where the M1/M2 macrophage ratio and basal ROS levels were significantly increased, while antioxidant defenses and angiogenesis were significantly decreased. Moreover, the expected increase in matrix metallopeptidase (MMP)-9 protein levels in diabetic conditions was not observed in KO mice, suggesting that the mechanisms leading to the increase in MMP-9 observed in diabetic wounds may in part be lymphocyte-dependent.
Significance: Our results indicate that lack of lymphocytes compromises wound healing independent of diabetes. The lack of these cells, even in non-diabetic mice, mimics the phenotype observed in wounds under diabetic conditions. Moreover, the combination of diabetes and the lack of lymphocytes, further impair the wound healing conditions, indicating that when the innate regulatory function is lost in these KO mice, excessive M1 polarization, poor angiogenesis and impaired wound healing are worsen.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
