β-Catenin–regulated myeloid cell adhesion and migration determine wound healing

Amini-Nik, Saeid; Cambridge, Elizabeth; Yu, Winston C Y; Guo, Anne; Whetstone, Heather; Nadesan, Puviindran; Poon, Raymond; Hinz, Boris; Alman, Benjamin A.

doi:10.1172/jci62059

Cited by 112 publications

(119 citation statements)

References 55 publications

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“…Macrophage-specific deletion of b-catenin in mice shows defects in migration and adhesion to fibroblasts and consequently inefficient skin wound healing. Macrophages overexpressing b-catenin rescued impaired wound-healing in irra diated mice (75). Rac1, another protein upregulated in normal rats during wound healing, participates in the coordinated and orchestrated process of wound healing.…”

Section: Interaction Among the Mirna Predicted Targets And Altered Womentioning

confidence: 98%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound-healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.

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Section: Interaction Among the Mirna Predicted Targets And Altered Womentioning

confidence: 98%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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“…Antibody staining was performed as described previously (14). Primary antibodies against perilipin, cleaved caspase-3 and CHOP were Cell Signaling products.…”

Section: Immunofluorescent Multichannel Staining Of Watmentioning

confidence: 99%

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Patsouris

Sadri

et al. 2015

Mol Med

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Extensively burned patients often suffer from sepsis, a complication that enhances postburn hypermetabolism and contributes to increased incidence of multiple organ failure, morbidity and mortality. Despite the clinical importance of burn sepsis, the molecular and cellular mechanisms of such infection-related metabolic derangements and organ dysfunction are still largely unknown. We recently found that upon endoplasmic reticulum (ER) stress, the white adipose tissue (WAT) interacts with the liver via inflammatory and metabolic signals leading to profound hepatic alterations, including hepatocyte apoptosis and hepatic fatty infiltration. We therefore hypothesized that burn plus infection causes an increase in lipolysis of WAT after major burn, partially through induction of ER stress, contributing to hyperlipidemia and profound hepatic lipid infiltration. We used a two-hit rat model of 60% total body surface area scald burn, followed by intraperitoneal (IP) injection of Pseudomonas Aeruginosa-derived lipopolysaccharide (LPS) 3 d postburn. One day later, animals were euthanized and liver and epididymal WAT (EWAT) samples were collected for gene expression, protein analysis and histological study of inflammasome activation, ER stress, apoptosis and lipid metabolism. Our results showed that burn plus LPS profoundly increased lipolysis in WAT associated with significantly increased hepatic lipid infiltration. Burn plus LPS augmented ER stress by upregulating CHOP and activating ATF6, inducing NLRP3 inflammasome activation and leading to increased apoptosis and lipolysis in WAT with a distinct enzymatic mechanism related to inhibition of AMPK signaling. In conclusion, burn sepsis causes profound alterations in WAT and liver that are associated with changes in organ function and structure.

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“…They modulate two signaling pathways: the canonical (b-catenin-dependent) and the noncanonical (b-catenin-independent) pathways (20). The Wnt/b-catenin pathway, implicated in wound healing (21), has been linked to the regulation of fibrogenesis (22,23). This signaling pathway is involved in patients with SSc because it is overexpressed in human skin where it activates fibroblasts and promotes their differentiation into myofibroblasts (24,25).…”

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confidence: 99%

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

Morin

Kavian

Nicco

et al. 2016

The Journal of Immunology

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Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy, and immunological abnormalities. Recent insights on the implication of STAT3, AKT, and Wnt/β-catenin in fibrosis have prompted us to investigate, in a mouse model of ROS-induced SSc, the effects of niclosamide, an antihelmintic drug that inhibits both of these signaling pathways. SSc was induced in BALB/c mice by daily s.c. injections of hypochlorous acid (HOCl). Mice were treated or not every other day, 5 d a week, for 6 wk, by niclosamide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 autoantibodies. STAT3, AKT, and Wnt/β-catenin pathways were hyperactivated in the skin and the lungs of diseased mice. Niclosamide reversed fibrosis of the skin and the lungs. Beneficial immunological effects were also observed because niclosamide decreased the activation of CD4+ and CD8+ T cells, autoimmune B cell activation, as well as IL-4 and IL-13 production in the skin. The improvement permitted by niclosamide in the mouse model of HOCl-induced SSc as well as the well-documented safety profile of this drug provide a rationale for the evaluation of niclosamide in the management of patients affected by this disease.

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β-Catenin–regulated myeloid cell adhesion and migration determine wound healing

Cited by 112 publications

References 55 publications

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

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