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Role of Toll-like Receptor 4 in Skeletal Muscle Damage in Chronic Limb Threatening Ischaemia

Navi, Ali; Hemanshu, Patel; Shiwen, Xu; Daryll, Baker; Abraham, David; Tsui, Janice; (2024) Role of Toll-like Receptor 4 in Skeletal Muscle Damage in Chronic Limb Threatening Ischaemia. JVS - Vascular Science , 5 , Article 100194. 10.1016/j.jvssci.2024.100194. Green open access

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Abstract

Objective: Toll-like receptors (TLR) are key pattern recognition receptors in the innate immune system. In particular, the TLR4-mediated immune response has been implicated in ischaemia-induced tissue injury. Mounting evidence supports a detrimental role of the innate immune system in the pathophysiology of skeletal muscle damage in patients with chronic limb-threatening ischaemia (CLTI), in whom patient-oriented functional outcomes are poor. The overall aim of this study was to investigate the potential role of TLR4 in skeletal muscle dysfunction and damage in CLTI.// Methods: The role of TLR4 in ischaemic muscle was investigated by 1) studying TLR4 expression and distribution in human gastrocnemius muscle biopsies 2) evaluating the functional consequences of TLR4 inhibition in myotubes derived from human muscle biopsies 3) assessing the therapeutic potential of modulating TLR4 signalling in ischaemic muscle in a mouse hind-limb ischaemia model.// Results: TLR4 was found to be expressed in human muscle biopsies, with significant upregulation in samples from patients with CLTI. In vitro studies using cultured human myotubes demonstrated upregulation of TLR4 in ischaemia, with activation of the downstream signalling pathway. Inhibition of TLR4 prior to ischaemia was associated with reduced ischaemia-induced apoptosis. Upregulation of TLR4 also occurred in ischaemia in vivo and TLR4 inhibition was associated with reduced inflammatory cell infiltration and diminished apoptosis in the ischaemic limb.// Conclusions: TLR4 is upregulated and activated in ischaemic skeletal muscle in patients with CLTI. Modulating TLR4 signalling in vitro and in vivo was associated with attenuation of ischaemia-induced skeletal muscle damage. This strategy could be explored further for potential clinical application.

Type: Article
Title: Role of Toll-like Receptor 4 in Skeletal Muscle Damage in Chronic Limb Threatening Ischaemia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jvssci.2024.100194
Publisher version: https://doi.org/10.1016/j.jvssci.2024.100194
Language: English
Additional information: Copyright © 2024 by the Society for Vascular Surgery. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
Keywords: Peripheral Arterial Disease (PAD), Critical Limb Threatening, Ischaemia (CLTI), Skeletal Muscle, Toll-like receptor (TLR), Inflammation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10187356
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