An Epidermal-Specific Role for Arginase1 during Cutaneous Wound Repair

Crompton, Rachel A.; Williams, Helen; Campbell, Laura; Lim, Hui Kheng; Saville, Charis R; Ansell, David M.; Reid, Adam J.; Wong, Jason; Vardy, Leah A.; Hardman, Matthew J.; Cruickshank, Sheena M.

doi:10.1016/j.jid.2021.09.009

Cited by 11 publications

(13 citation statements)

References 59 publications

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“…We report that aged rat vaginal wounds show delayed healing and significantly reduced Arg1 expression versus young rat wounds. These data are in line with previous studies showing reduced Arg1 in the dermis and epidermis of aged murine wounds ( 24 , 25 ), and reduced Arg1 expression in acute wounds of the elderly ( 23 ). It is widely recognised that ageing is associated with a decrease in serum 17β-estradiol ( 39 ), while estrogen deficiency correlates more convincingly with delayed healing than chronological age ( 23 ).…”

Section: Discussionsupporting

confidence: 93%

“…Here, breaking stress (N/m 2 ) was 75% lower in the healed wounds of aged versus young rats ( P < 0.001; Figure 1B ). We next measured the levels of Arg1 in vaginal wounds due to its pertinent roles in skin repair ( 24 , 25 ). Throughout the course of healing, epithelial Arg1 expression increased, with the highest levels observed in both young and aged wounds at day 7 post-injury ( P < 0.001).…”

Section: Resultsmentioning

confidence: 99%

“…It is clear that impaired Arg1 is a contributing factor to delayed healing, as Arg1 is downregulated in delayed healing aged wounds ( 23 , 24 ), and both genetic knockdown and chemical inhibition of Arg1 increase inflammation and delay repair ( 24 , 25 ). In addition, previous authors have demonstrated L-arginine supplementation improves healing in diabetic skin wounds in vivo and may be beneficial in patients with diabetic foot ulcers ( 60 – 62 ).…”

Section: Discussionmentioning

confidence: 99%

“…Excessive production of iNOS , and reduced expression of ARG1 , are associated with delayed healing in the elderly ( 23 ), while specific ablation of dermal Arg1 impairs skin repair ( 24 ). Much of the focus of Arg1 in wound healing is related to its macrophage-specific effects, yet recent findings have revealed a role for epidermal Arg1 in modulating effective skin repair ( 25 ). Given the number of studies addressing ageing and Arg1 in skin healing, it is surprising that reference to the contribution of these factors to repair in other tissues remains limited ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

et al. 2022

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Pelvic organ prolapse is a disorder that substantially affects the quality of life of millions of women worldwide. The greatest risk factors for prolapse are increased parity and older age, with the largest group requiring surgical intervention being post-menopausal women over 65. Due to ineffective healing in the elderly, prolapse recurrence rates following surgery remain high. Therefore, there is an urgent need to elucidate the cellular and molecular drivers of poor healing in pelvic floor dysfunction to allow effective management and even prevention. Recent studies have uncovered the importance of Arginase 1 for modulating effective healing in the skin. We thus employed novel in vitro and in vivo vaginal injury models to determine the specific role of Arginase 1 in age-related vaginal repair. Here we show, for the first time, that aged rat vaginal wounds have reduced Arginase 1 expression and delayed healing. Moreover, direct inhibition of Arginase 1 in human vaginal epithelial cells also led to delayed scratch-wound closure. By contrast, activation of Arginase 1 significantly accelerated healing in aged vaginal wounds in vivo, to rates comparable to those in young animals. Collectively, these findings reveal a new and important role for Arginase 1 in mediating effective vaginal repair. Targeting age-related Arginase 1 deficiency is a potential viable therapeutic strategy to promote vaginal healing and reduce recurrence rate after surgical repair of pelvic organ prolapse.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

et al. 2022

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“…Further, histological analysis showed that Arg1 expression was significantly decreased in the granulation tissues of Mafb f/f ::LysM-Cre mice on days 3 and 5 ( Figure 4 D). Arg1 is also expressed at high levels in keratinocytes and especially in those at wound edges [ 27 ]. The edges of the wound tissues used in RT-qPCR ( Figure 4 B) probably contained keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-Specific, Mafb-Deficient Mice Showed Delayed Skin Wound Healing

Inoue

Liao

Tsunakawa

et al. 2022

IJMS

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Macrophages play essential roles throughout the wound repair process. Nevertheless, mechanisms regulating the process are poorly understood. MAFB is specifically expressed in the macrophages in hematopoietic tissue and is vital to homeostatic function. Comparison of the skin wound repair rates in macrophage-specific, MAFB-deficient mice (Mafbf/f::LysM-Cre) and control mice (Mafbf/f) showed that wound healing was significantly delayed in the former. For wounded GFP knock-in mice with GFP inserts in the Mafb locus, flow cytometry revealed that their GFP-positive cells expressed macrophage markers. Thus, macrophages express Mafb at wound sites. Immunohistochemical (IHC) staining, proteome analysis, and RT-qPCR of the wound tissue showed relative downregulation of Arg1, Ccl12, and Ccl2 in Mafbf/f::LysM-Cre mice. The aforementioned genes were also downregulated in the bone marrow-derived, M2-type macrophages of Mafbf/f::LysM-Cre mice. Published single-cell RNA-Seq analyses showed that Arg1, Ccl2, Ccl12, and Il-10 were expressed in distinct populations of MAFB-expressing cells. Hence, the MAFB-expressing macrophage population is heterogeneous. MAFB plays the vital role of regulating multiple genes implicated in wound healing, which suggests that MAFB is a potential therapeutic target in wound healing.

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Ablative fractional CO₂ laser treatment promotes wound healing phenotype in skin macrophages

Wiinberg,

Andresen,

Haedersdal

et al. 2024

Lasers Surg Med

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ObjectivesAblative fractional laser (AFL) treatment is a well‐established method for reducing signs of skin photoaging. However, the biological mechanisms underlying AFL‐induced healing responses and skin rejuvenation remain largely unknown. It is known that macrophages play an important role in orchestrating healing, normalization, and remodeling processes in skin. Macrophage phenotypes are characterized by inflammatory markers, including arginase‐1 (Arg1), major histocompatibility class II molecules (MHC II), and CD206. This study aims to explore AFL's effect on macrophage phenotype by evaluating changes in inflammatory markers and the potential concurrent accumulation of Arg1 in the skin.MethodsMice (n = 9) received a single AFL treatment on the left side of the back skin (100 mJ/microbeam, 5% density) while the right side of the back remained untreated as control. Treated and untreated skin from each mouse were collected Day 5 posttreatment for flow cytometry and histology analysis. Flow cytometry evaluated the immune infiltration of macrophages and the expression of macrophage inflammatory markers (Arg1, MHC II, and CD206). In addition, Arg1 presence in the skin was evaluated through antibody staining of histology samples and quantification was performed using QuPath image analysis software.ResultsFollowing AFL, the number of macrophages increased 11‐fold (p = 0.0053). Phenotype analysis of AFL‐treated skin revealed an increase in the percentage of macrophages positive for Arg1 (p < 0.0001) and a decrease in the percentage of macrophages positive for MHC II (p < 0.0001) compared to untreated skin. No significant differences were observed in percentage of CD206‐positive macrophages (p = 0.8952). Visualization of AFL‐treated skin demonstrated a distinct pattern of Arg1 accumulation that correlated with the microscopic treatment zones (MTZ). Quantification of the percentage of Arg1‐positive area in epidermis and dermis showed a significant increase from 3.5% ± 1.2% to 5.2% ± 1.7 (p = 0.0232) and an increase from 2.2% ± 1.2% to 9.6% ± 3.3 (p < 0.0001) in whole skin samples.ConclusionAFL treatment polarizes macrophages toward a wound healing phenotype and induces Arg1 accumulation in the MTZ. We propose that the polarized wound healing macrophages are a major source for the increased Arg1 levels observed in the skin following treatment.

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An Epidermal-Specific Role for Arginase1 during Cutaneous Wound Repair

Cited by 11 publications

References 59 publications

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

Macrophage-Specific, Mafb-Deficient Mice Showed Delayed Skin Wound Healing

Ablative fractional CO₂ laser treatment promotes wound healing phenotype in skin macrophages

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An Epidermal-Specific Role for Arginase1 during Cutaneous Wound Repair

Cited by 11 publications

References 59 publications

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

Epithelial arginase-1 is a key mediator of age-associated delayed healing in vaginal injury

Macrophage-Specific, Mafb-Deficient Mice Showed Delayed Skin Wound Healing

Ablative fractional CO2 laser treatment promotes wound healing phenotype in skin macrophages

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Ablative fractional CO₂ laser treatment promotes wound healing phenotype in skin macrophages