Vγ4 T Cells Inhibit the Pro-healing Functions of Dendritic Epidermal T Cells to Delay Skin Wound Closure Through IL-17A

Li, Yashu; Wang, Yangping; Zhou, Lei; Liu, Meixi; Liang, Guangping; Yan, Rongshuai; Jiang, Yufeng; Hao, Jianlei; Zhang, Xiaorong; Hu, Xiaohong; Huang, Yong; Wang, Rupeng; Yin, Zhinan; Wu, Jun; Luo, Gaoxing; Wang, He

doi:10.3389/fimmu.2018.00240

Cited by 42 publications

(66 citation statements)

References 38 publications

(85 reference statements)

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“…Vγ4 T cells have been reported to participate in autoimmune diseases and skin graft rejection at the early stages by producing IL-17A ( 10 , 33 , 62 , 66 ). IFN-γ-positive Vγ4 T cells play a protective role in antitumor immunity, but they do not contribute in skin transplantation and wound healing ( 10 , 33 , 67 ). Which cytokine Vγ4 T cells secrete may depend on local circumstances.…”

Section: Vγ4 T Cells Provide the Major Source Of Il-17a At The Early mentioning

confidence: 99%

“…Furthermore, we have reported recently that Vγ4 T cells provide a major source of IL-17A in the epidermis at the early stages of wounding. Approximately half of the epidermal IL-17A-positive cells are Vγ4 T cells after skin injury ( 67 ). IL-17A production in the epidermis is dramatically decreased after the depletion of Vγ4 T cells in wild-type mice, but it is significantly enhanced in Tcr δ − / − animals by the addition of freshly isolated Vγ4 T cells onto wound beds ( 67 ).…”

Section: Vγ4 T Cells Provide the Major Source Of Il-17a At The Early mentioning

confidence: 99%

“…Approximately half of the epidermal IL-17A-positive cells are Vγ4 T cells after skin injury ( 67 ). IL-17A production in the epidermis is dramatically decreased after the depletion of Vγ4 T cells in wild-type mice, but it is significantly enhanced in Tcr δ − / − animals by the addition of freshly isolated Vγ4 T cells onto wound beds ( 67 ). In addition, Vγ4 T cells also migrate to noninflamed skin and peripheral lymph nodes, and respond faster and stronger to a second imiquimod challenge ( 69 ).…”

Section: Vγ4 T Cells Provide the Major Source Of Il-17a At The Early mentioning

confidence: 99%

“…IL-17A has been demonstrated to act upstream to enhance epidermal IL-1β/IL-23 production in a skin graft transplantation model ( 10 ). Furthermore, IL-1β and IL-23 production in the epidermis of wound edges is weakened by a deficiency or blockage of IL-17A but enhanced by the addition of rIL-17A ( 67 ). Depletion of Vγ4 T cells reduces epidermal IL-1β/IL-23 production, but supplementing wild-type rather than Il-17a − / − Vγ4 T cells onto wound beds promotes epidermal IL-1β/IL-23 production in Tcr δ − / − mice ( 67 ).…”

Section: Vγ4 T Cell-derived Il-17a and Epidermal Il-1β/il-23 Form A Pmentioning

confidence: 99%

“…Furthermore, IL-1β and IL-23 production in the epidermis of wound edges is weakened by a deficiency or blockage of IL-17A but enhanced by the addition of rIL-17A ( 67 ). Depletion of Vγ4 T cells reduces epidermal IL-1β/IL-23 production, but supplementing wild-type rather than Il-17a − / − Vγ4 T cells onto wound beds promotes epidermal IL-1β/IL-23 production in Tcr δ − / − mice ( 67 ). Therefore, we regard that IL-17A secreted by Vγ4 T cells and IL-1β/IL-23 derived from epidermal cells may form a positive feedback loop in the epidermis around wounds to amplify local inflammation after skin injury.…”

Section: Vγ4 T Cell-derived Il-17a and Epidermal Il-1β/il-23 Form A Pmentioning

confidence: 99%

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Functions of Vγ4 T Cells and Dendritic Epidermal T Cells on Skin Wound Healing

Luo

et al. 2018

Front. Immunol.

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Wound healing is a complex and dynamic process that progresses through the distinct phases of hemostasis, inflammation, proliferation, and remodeling. Both inflammation and re-epithelialization, in which skin γδ T cells are heavily involved, are required for efficient skin wound healing. Dendritic epidermal T cells (DETCs), which reside in murine epidermis, are activated to secrete epidermal cell growth factors, such as IGF-1 and KGF-1/2, to promote re-epithelialization after skin injury. Epidermal IL-15 is not only required for DETC homeostasis in the intact epidermis but it also facilitates the activation and IGF-1 production of DETC after skin injury. Further, the epidermal expression of IL-15 and IGF-1 constitutes a feedback regulatory loop to promote wound repair. Dermis-resident Vγ4 T cells infiltrate into the epidermis at the wound edges through the CCR6-CCL20 pathway after skin injury and provide a major source of IL-17A, which enhances the production of IL-1β and IL-23 in the epidermis to form a positive feedback loop for the initiation and amplification of local inflammation at the early stages of wound healing. IL-1β and IL-23 suppress the production of IGF-1 by DETCs and, therefore, impede wound healing. A functional loop may exist among Vγ4 T cells, epidermal cells, and DETCs to regulate wound repair.

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Section: Vγ4 T Cells Provide the Major Source Of Il-17a At The Early mentioning

confidence: 99%

Section: Vγ4 T Cells Provide the Major Source Of Il-17a At The Early mentioning

confidence: 99%

Section: Vγ4 T Cells Provide the Major Source Of Il-17a At The Early mentioning

confidence: 99%

Section: Vγ4 T Cell-derived Il-17a and Epidermal Il-1β/il-23 Form A Pmentioning

confidence: 99%

Section: Vγ4 T Cell-derived Il-17a and Epidermal Il-1β/il-23 Form A Pmentioning

confidence: 99%

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Functions of Vγ4 T Cells and Dendritic Epidermal T Cells on Skin Wound Healing

Luo

et al. 2018

Front. Immunol.

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IL-1β/NF-κB signaling inhibits IGF-1 production via let-7f-5p in dendritic epidermal T cells

Wang

et al. 2022

Journal of Leukocyte Biology

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Dendritic epidermal T cells (DETCs) are the main source of insulin‐like growth factor‐1 (IGF‐1) in epidermal tissue, which promote re‐epithelialization and wound healing. In refractory wounds, IL‐1β has been shown to activate NF‐κB and suppress IGF‐1 expression in DETCs. Nevertheless, the underlying mechanisms remain unclear. In this study, chromatin immunoprecipitation analysis revealed that IL‐1β did not inhibit NF‐κB binding to IGF‐1 promoter, indicating that IL‐1β/NF‐κB may suppress IGF‐1 expression by alternative mechanisms. MiRNAs negatively regulate gene expression predominantly by base pairing to the 3′ untranslation region (UTR) of target mRNAs. Let‐7f‐5p, miR‐1a‐3p, and miR‐98‐5p have been identified as IGF‐1‐specific miRNAs that can bind directly to the 3′UTR of IGF‐1 mRNA and dysregulate IGF‐1 mRNA and protein levels. In IL‐1β‐treated epidermis around wounds or DETCs in vitro, NF‐κB promoted the expression of let‐7f‐5p, and IGF‐1 expression was impeded via NF‐κB/let‐7f‐5p pathway. As pre‐let‐7f‐5p, let‐7f‐1 is located in the 3′UTR of LOC118568094, and let‐7f‐2 is located in the intron of HUWE1. We discovered that NF‐κB p65 bound to the promoters of LOC118568094 and HUWE1 to accelerate let‐7f‐5p expression, but NF‐κB p65 did not affect the methylation levels of LOC118568094 and HUWE1 CpG islands. Injections of Let‐7f‐5p antagomir into IL‐1β‐treated and ischemic wound margins restored IGF‐1 secretion in DETCs and promoted wound healing. In conclusion, we demonstrated that NF‐κB signaling pathway activated by IL‐1β could increase let‐7f‐5p expression to inhibit IGF‐1 production in DETCs and delay wound healing. And let‐7f‐5p antagomir utilized in wound margin could effectively promote refractory wound healing.

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Interleukin‐17 as a spatiotemporal bridge from acute to chronic inflammation: Novel insights from computational modeling

Shah

Zamora

Vodovotz

2023

WIREs Mechanisms of Disease

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A systematic review of several acute inflammatory diseases ranging from sepsis and trauma/hemorrhagic shock to the relevant pathology of the decade, COVID‐19, points to the cytokine interleukin (IL)‐17A as being centrally involved in the propagation of inflammation. We summarize the role of IL‐17A in acute inflammation, leveraging insights made possible by biological network analysis and novel computational methodologies aimed at defining the spatiotemporal spread of inflammation in both experimental animal models and humans. These studies implicate IL‐17A in the cross‐tissue spread of inflammation, a process that appears to be in part regulated through neural mechanisms. Although acute inflammatory diseases are currently considered distinct from chronic inflammatory pathologies, we suggest that chronic inflammation may represent repeated, cyclical episodes of acute inflammation driven by mechanisms involving IL‐17A. Thus, insights from computational modeling of acute inflammatory diseases may improve diagnosis and treatment of chronic inflammation; in turn, therapeutics developed for chronic/autoimmune disease may be of benefit in acute inflammation. This article is categorized under: Immune System Diseases > Computational Models

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Vγ4 T Cells Inhibit the Pro-healing Functions of Dendritic Epidermal T Cells to Delay Skin Wound Closure Through IL-17A

Cited by 42 publications

References 38 publications

Functions of Vγ4 T Cells and Dendritic Epidermal T Cells on Skin Wound Healing

Functions of Vγ4 T Cells and Dendritic Epidermal T Cells on Skin Wound Healing

IL-1β/NF-κB signaling inhibits IGF-1 production via let-7f-5p in dendritic epidermal T cells

Interleukin‐17 as a spatiotemporal bridge from acute to chronic inflammation: Novel insights from computational modeling

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