Toll-like receptors 2 and 6 mediate apoptosis and inflammation in ischemic skeletal myotubes

Patel, Hemanshu; Yong, Cissy; Navi, Ali; Shaw, Sidney; Xu, Shiwen; Abraham, David; Baker, DM; Tsui, Janice

doi:10.1177/1358863x19843180

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…Other groups have shown high glucose increases TLR4 mediated inflammation; however, the novel observation from this study is the effect of adding a second noxious variable, hypoxia. This group has previously shown hypoxia induces TLRs 2, 6, and 4 expression and activation in skeletal muscle; 29 however, it has now been demonstrated in dermal fibroblasts there is a significant increase in TLR4 expression and activation in hypoxia with concurrent exposure to high glucose. This inflammatory effect signals via TLR4 pathways, resulting in increased inflammation via downstream production of cytokines such as IL-6.…”

Section: Discussionmentioning

confidence: 95%

Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model

Portou

Baker

et al. 2020

European Journal of Vascular and Endovascular Surgery

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The effect of hyperglycaemia on pro-inflammatory pattern recognition receptors in human cells, including fibroblasts has been demonstrated previously; however, this study is the first to combine diabetic conditions with ischaemia. This study offers a mechanism of pathological overexpression and activation of innate immune pattern recognition receptors such as Toll-like receptor 4, leading to hyperinflammatory responses, through exposure to hyperglycaemia. This excess inflammation leads to the rapidly progressive destructive acute, and subsequently chronic, inflammation leading to non-healing wounds that occur in diabetic patients often with coexisting ischaemia. It provides the first evidence of a synergistic relationship between hyperglycaemia and ischaemia and suggests a possible explanation for the observation that clinical outcomes are significantly worse in diabetic patients in other ischaemic pathologies. Objective: Diabetes mellitus has reached epidemic proportions. Foot ulceration is a multifactorial complication of diabetes associated with marked morbidity and mortality. Innate immune Toll-like receptor 4 (TLR4) mediated inflammation has been implicated in the systemic pathogenesis of diabetes and may contribute to impairment of wound healing. This study investigates the effect of high glucose and hypoxic conditions on TLR4 activation and signalling in vitro and in vivo. Methods: Fibroblasts cultured at physiological glucose concentration (5.5 mM) were exposed to glucose concentrations from 0 mM to 25 mM, with duplicates placed in a hypoxic chamber. TLR4 inhibition was assessed in the 25 mM glucose groups. Diabetes was induced in wild type (WT) and TLR4 knockout (KO) C57BL/6 mice by intraperitoneal injection of low dose streptozocin (STZ). Hindlimb ischaemia was induced by femoral artery ligation four weeks post streptozocin, and a full thickness 4 mm skin wound inflicted below the knee. Wound healing was assessed via digital planimetry on days 3, 7, and 14 post surgery. Results: Hypoxic and high glucose (25 mM) conditions led to an increase in TLR4 protein expression, apoptosis, and interleukin (IL)-6 release. Inhibition with a TLR4 neutralising antibody and specific TLR4 antagonist ameliorated the effects of high glucose and ischaemia (p < .05). In vivo, wound healing was significantly impaired in the diabetic ischaemic group at day 14 (p < .05). Diabetic ischaemic wounds in TLR4 KO mice exhibited significantly improved healing rates compared with those in WT mice at all time points. Conclusion: Hypoxia stimulates upregulation of TLR4 protein expression and this effect is exaggerated by hyperglycaemia. In TLR4 KO mice, there is a significant improvement in the healing of diabetic ischaemic wounds compared with WT. It is suggested that a synergistic effect between hypoxia and hyperglycaemia impairing wound healing exists, through TLR4 mediated inflammation.

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Section: Discussionmentioning

confidence: 95%

Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model

Portou

Baker

et al. 2020

European Journal of Vascular and Endovascular Surgery

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“…Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced, sterile, and ischemic injury-induced inflammation. 4,27 Endogenous ligands such as low-molecular hyaluronic acid, fibronectin, heat shock proteins, and heparin sulfate were found to be cleaved in inflamed tissue and to activate TLR2 and TLR4, initiating an inflammatory response even in the absence of pathogens and infiltrating immune cells. Both macrotrauma and microtrauma conditions occur in skeletal muscle injury.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Myogenesis Induced by Ultrasound Exposure in a Volumetric Skeletal Muscle Loss Injury Model

Mohamad Yusoff,

Nakashima,

Kajikawa

et al. 2023

Am J Sports Med

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Background: Low-intensity pulsed ultrasound (LIPUS) irradiation has been shown to induce various responses in different cells. It has been shown that LIPUS activates extracellular signal–regulated kinase 1/2 (ERK1/2) through integrin. Purpose: To study the effects of LIPUS on myogenic regulatory factors and other related myogenesis elements in a volumetric skeletal muscle loss injury model. Study Design: Controlled laboratory study. Methods: C57BL/6J mice were subjected to full-thickness muscle defect injury of the quadriceps and treated with direct application of LIPUS 20 min/d or non-LIPUS treatment (control) for 3, 7, and 14 days. LIPUS was also applied to C2C12 cells in culture in the presence of low and high doses of lipopolysaccharides. The expression levels of myogenic regulatory factors and the expression levels of myokine-related and angiogenic-related proteins of the control and LIPUS groups were analyzed. Results: Muscle volume in the injury site was restored at day 14 with LIPUS treatment. Paired-box protein 7, myogenic factor 5, myogenin, and desmin expressions were significantly different between control and LIPUS groups at days 7 and 14. Myokine and angiogenic cytokine-related factors were significantly increased in the LIPUS group at day 3 and decreased with no significant difference between the groups by day 14. LIPUS induced different responses of myogenic regulatory factors in C2C12 cells with low and high doses of lipopolysaccharides. LIPUS promoted myogenesis through short-lived increase in interleukin-6 and heme oxygenase 1, together with activation of ERK1/2. Conclusion: LIPUS had a constant effect on the variables of tissue damage, from macrotrauma to microtrauma, leading to efficient muscle regeneration. Clinical Relevance: The focus of therapeutic strategies with LIPUS has been not only for microvascular regeneration but also for skeletal muscle and related local tissue recovery from acute or chronic damage.

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“…Emerging evidence suggested that inflammation plays an important role in the progress of CLI ( 4 , 5 ). In support of this theory, it was shown that the circulating levels of cytokines (IL-6 and TNFα), adhesion molecules (VCAM-1 and ICAM-1), and selectins in patients with peripheral arterial disease are elevated ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…There are numerous theories about the CLI etiology, including lipid deposition, inflammation, and thrombosis ( 2 , 3 ). Kinds of inflammatory factors and cytokines are involved in inflammatory injury, plaque formation, plaque rupture, and final artery stenosis or occlusion ( 4 , 5 ). Patients with peripheral arterial diseases often have accompanying kinds of severe comorbidities, including coronary artery disease, cerebrovascular disease, respiratory dysfunction, and end-stage renal disease ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis

Liu

Cheng

et al. 2021

Front. Cardiovasc. Med.

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Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration, and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. The circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes play a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that the circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipid metabolism, inflammation, and angiogenesis. A hindlimb ischemia model performed in wild-type and Bmal1−/− mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that the decreased expression of Bmal1 would increase ox-LDL uptake and impair endothelial cell functions, including proliferation, migration, and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipid uptake and by activating IL-10 transcription and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that the circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.

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Toll-like receptors 2 and 6 mediate apoptosis and inflammation in ischemic skeletal myotubes

Cited by 5 publications

References 33 publications

Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model

Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model

Therapeutic Myogenesis Induced by Ultrasound Exposure in a Volumetric Skeletal Muscle Loss Injury Model

Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis

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