Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

Cheng, Tsung Lin; Lai, Chao Han; Chen, Po Ku; Cho, Chia Fong; Hsu, Yun Yan; Wang, Kuan Chieh; Lin, Wei; Chang, Bi Ing; Liu, Shikai; Wu, Yu; Hsu, Chao Kai; Shi, Guey Yueh; Wu, Hua

doi:10.1038/jid.2015.32

Cited by 21 publications

(19 citation statements)

References 35 publications

(37 reference statements)

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“…In this study, assessments of functional healing demonstrated that small 3 mm diameter excisional and incisional wounds healed nearly normally in Mac‐1 −/− mice, with normal wound closure, normal collagen content, and normal wound breaking strength. The small excisional skin wounds utilized here do heal with substantial contraction, although reepithelialization does contribute to wound closure in this model . Considered in context of prior studies, our results suggest that wounds that heal with contraction, such as the 3mm excisional wounds, and wounds that heal by primary intention, such as incisional wounds, may more easily overcome genetic or other wound healing deficits.…”

Section: Discussionsupporting

confidence: 51%

Wound healing in Mac‐1 deficient mice

Chen

Nagaraja

Zhou

et al. 2017

Wound Repair Regeneration

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Mac-1 (CD11b/CD18) is a macrophage receptor that plays several critical roles in macrophage recruitment and activation. Because macrophages are essential for proper wound healing, the impact of Mac-1 deficiency on wound healing is of significant interest. Prior studies have shown that Mac-1−/− mice exhibit deficits in healing, including delayed wound closure in scalp and ear wounds. The current study examined whether Mac-1 deficiency influences wound healing in small excisional and incisional skin wounds. Three millimeter diameter full thickness excisional wounds and incisional wounds were prepared on the dorsal skin of Mac-1 deficient (Mac-1 −/−) and wild type (WT) mice, and wound healing outcomes were examined. Mac-1 deficient mice exhibited a normal rate of wound closure, generally normal levels of total collagen, and nearly normal synthesis and distribution of collagens I and III. In incisional wounds, wound breaking strength was similar for Mac-1 −/− and WT mice. Wounds of Mac-1 deficient mice displayed normal total macrophage content, although macrophage phenotype markers were skewed as compared to WT. Interestingly, amounts of TGF-β1 and its downstream signaling molecules, SMAD2 and SMAD3, were significantly decreased in the wounds of Mac-1 deficient mice compared to WT. The results suggest that Mac-1 deficiency has little impact on the healing of small excisional and incisional wounds. Moreover, the findings demonstrate that the effect of single genetic deficiencies on wound healing may markedly differ among wound models. These conclusions have implications for the interpretation of the many prior studies that utilize a single model system to examine wound healing outcomes in genetically deficient mice.

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Section: Discussionsupporting

confidence: 51%

Wound healing in Mac‐1 deficient mice

Chen

Nagaraja

Zhou

et al. 2017

Wound Repair Regeneration

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“…Previous reports have demonstrated that long-standing diabetes results in osteoporosis in rats, and diabetic patients have a high risk for osteoporotic fractures 30 31 . Other studies have indicated that a high-glucose environment may activate NF-κB, which may suppress TM expression 32 33 . These findings suggested that diseases with suppressed TM expression may increase osteoporosis risk.…”

Section: Discussionmentioning

confidence: 99%

Myeloid thrombomodulin lectin-like domain inhibits osteoclastogenesis and inflammatory bone loss

Cheng

Lai

Shieh

et al. 2016

Sci Rep

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Osteoclastogenesis is an essential process during bone metabolism which can also be promoted by inflammatory signals. Thrombomodulin (TM), a transmembrane glycoprotein, exerts anti-inflammatory activities such as neutralization of proinflammatory high-mobility group box 1 (HMGB1) through TM lectin-like domain. This study aimed to identify the role of myeloid TM (i.e., endogenous TM expression on the myeloid lineage) in osteoclastogenesis and inflammatory bone loss. Using human peripheral blood mononuclear cells and mouse bone marrow-derived macrophages, we observed that the protein levels of TM were dramatically reduced as these cells differentiated into osteoclasts. In addition, osteoclastogenesis and extracellular HMGB1 accumulation were enhanced in primary cultured monocytes from myeloid-specific TM-deficient mice (LysMcre/TMflox/flox) and from TM lectin-like domain deleted mice (TMLeD/LeD) compared with their respective controls. Micro-computerized tomography scans showed that ovariectomy-induced bone loss was more pronounced in TMLeD/LeD mice compared with controls. Finally, the inhibiting effects of recombinant TM lectin-like domain (rTMD1) on bone resorption in vitro, and bone loss in both the ovariectomized model and collagen antibody-induced arthritis model has been detected. These findings suggested that the myeloid TM lectin-like domain may inhibit osteoclastogenesis by reducing HMGB1 signaling, and rTMD1 may hold therapeutic potential for inflammatory bone loss.

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“…Although this study produces insight into the mechanism behind TLR4 and myeloid inflammation in cutaneous wound healing, some limitations must be addressed. Myeloid cells play an important role in tissue repair following injury; however, there is evidence that TLR4 is also expressed in keratinocytes, fibroblasts, and B cells (49,51). This may partially explain why the adoptive transfer of myeloid-specific TLR4 cells partially restores wound healing, as TLR4 may also regulate other cell types, including epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury

Davis

Kimball

denDekker

et al. 2019

The Journal of Immunology

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Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1 f/f Lyz2 Cre+) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4 2/2), Myd88 (Myd88 2/2), and myeloid-specific Tlr4 (Tlr4 f/f Lyz2 Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4 2/2 and Myd88 2/2 wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wildtype mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.

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Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

Cited by 21 publications

References 35 publications

Wound healing in Mac‐1 deficient mice

Wound healing in Mac‐1 deficient mice

Myeloid thrombomodulin lectin-like domain inhibits osteoclastogenesis and inflammatory bone loss

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury

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