PMID- 38510939
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240322
IS  - 2666-3503 (Electronic)
IS  - 2666-3503 (Linking)
VI  - 5
DP  - 2024
TI  - Role of toll-like receptor 4 in skeletal muscle damage in chronic 
      limb-threatening ischemia.
PG  - 100194
LID - 10.1016/j.jvssci.2024.100194 [doi]
LID - 100194
AB  - OBJECTIVE: Toll-like receptors (TLRs) are key pattern recognition receptors in 
      the innate immune system. In particular, the TLR4-mediated immune response has 
      been implicated in ischemia-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 ischemia (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 ischemic 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, and (3) assessing the therapeutic 
      potential of modulating TLR4 signaling in ischemic muscle in a mouse hindlimb 
      ischemia 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 
      ischemia, with activation of the downstream signaling pathway. Inhibition of TLR4 
      before ischemia was associated with reduced ischemia-induced apoptosis. 
      Upregulation of TLR4 also occurred in ischemia in vivo and TLR4 inhibition was 
      associated with decreased inflammatory cell infiltration and diminished apoptosis 
      in the ischemic limb. CONCLUSIONS: TLR4 is upregulated and activated in ischemic 
      skeletal muscle in patients with CLTI. Modulating TLR4 signaling in vitro and 
      in vivo was associated with attenuation of ischemia-induced skeletal muscle 
      damage. This strategy could be explored further for potential clinical 
      application.
CI  - (c) 2024 by the Society for Vascular Surgery. Published by Elsevier Inc.
FAU - Navi, Ali
AU  - Navi A
AD  - Division of Surgery & Interventional Science, University College London, London, 
      United Kingdom.
FAU - Patel, Hemanshu
AU  - Patel H
AD  - Division of Surgery & Interventional Science, University College London, London, 
      United Kingdom.
FAU - Shiwen, Xu
AU  - Shiwen X
AD  - Centre for Rheumatology & Connective Tissue Disease, University College London, 
      London, United Kingdom.
FAU - Baker, Daryll
AU  - Baker D
AD  - Division of Surgery & Interventional Science, University College London, London, 
      United Kingdom.
FAU - Abraham, David
AU  - Abraham D
AD  - Centre for Rheumatology & Connective Tissue Disease, University College London, 
      London, United Kingdom.
FAU - Tsui, Janice
AU  - Tsui J
AD  - Division of Surgery & Interventional Science, University College London, London, 
      United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20240211
PL  - United States
TA  - JVS Vasc Sci
JT  - JVS-vascular science
JID - 101767073
PMC - PMC10951510
OTO - NOTNLM
OT  - Critical limb-threatening ischemia (CLTI)
OT  - Inflammation
OT  - Peripheral arterial disease (PAD)
OT  - Skeletal muscle
OT  - Toll-like receptor (TLR)
COIS- None.
EDAT- 2024/03/21 06:43
MHDA- 2024/03/21 06:44
PMCR- 2024/02/11
CRDT- 2024/03/21 04:18
PHST- 2023/10/03 00:00 [received]
PHST- 2024/02/06 00:00 [accepted]
PHST- 2024/03/21 06:44 [medline]
PHST- 2024/03/21 06:43 [pubmed]
PHST- 2024/03/21 04:18 [entrez]
PHST- 2024/02/11 00:00 [pmc-release]
AID - S2666-3503(24)00005-1 [pii]
AID - 100194 [pii]
AID - 10.1016/j.jvssci.2024.100194 [doi]
PST - epublish
SO  - JVS Vasc Sci. 2024 Feb 11;5:100194. doi: 10.1016/j.jvssci.2024.100194. 
      eCollection 2024.