Toll-Like Receptors Differentially Regulate CC and CXC Chemokines in Skeletal Muscle via NF- B and Calcineurin

Respiratory Division, Room L411, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
Infection and Immunity (Impact Factor: 4.16). 01/2007; 74(12):6829-38. DOI: 10.1128/IAI.00286-06
Source: PubMed

ABSTRACT Immunologically active molecules such as cytokines and chemokines have been implicated in skeletal muscle weakness during sepsis as well as recovery from muscle injury. In sepsis, Toll-like receptors (TLRs) act as key sentinel molecules of the innate immune system. Here we determined skeletal muscle cell responses of two prototypical CC and CXC chemokine genes (monocyte chemoattractant protein 1 [MCP-1] and KC, respectively), to stimulation with specific TLR ligands. In addition, we examined whether NF-kappaB and calcineurin signaling are involved in these responses. Differentiated myotubes and intact whole muscles expressed TLR2, TLR4, TLR5, and TLR9. Stimulation with ligands for TLR2 (peptidoglycan) or TLR4 (LPS) elicited robust and equivalent levels of MCP-1 and KC mRNA expression, whereas stimulation of TLR5 (by flagellin) required gamma interferon priming to induce similar effects. Although both TLR2 and TLR4 ligands activated the NF-kappaB pathway, NF-kappaB reporter activity was approximately 20-fold greater after TLR4 stimulation than after TLR2 stimulation. Inhibitory effects of NF-kappaB blockade on TLR-mediated chemokine gene expression, by either pharmacological (pyrrolidine dithiocarbamate) or molecular (IKKbeta dominant-negative transfection) methods, were also more pronounced during TLR4 stimulation. In contrast, inhibitory effects on TLR-mediated chemokine expression of calcineurin blockade (by FK506) were greater for TLR2 than for TLR4 stimulation. MCP-1 and KC mRNA levels also demonstrated differential responses to NF-kappaB and calcineurin blockade during stimulation with specific TLR ligands. We conclude that skeletal muscle cells differentially utilize the NF-kappaB and calcineurin pathways in a TLR-specific manner to enable complex regulation of CC and CXC chemokine gene expression.

Download full-text


Available from: Basil Petrof, Apr 13, 2014
  • Source
    • "TLRs are expressed on multiple cell types (such as dendritic cells and macrophages) and generally respond to " danger signals " (e.g., pathogens and damage associated molecules) triggering the production of inflammatory cytokines and chemokines. In vitro studies demonstrated that murine myotubes express TLR2, TLR4, TLR5, and TLR9 [53]. Notably, a study showed that TLR3 is expressed in muscle biopsies of patients with chronic myopathies and that TLR3 activation on human myoblasts triggers a downstream cascade leading to NF-í µí¼…B activation and ultimately IL-8 production [54]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treating muscle disorders poses several challenges to the rapidly evolving field of regenerative medicine. Considerable progress has been made in isolating, characterizing, and expanding myogenic stem cells and, although we are now envisaging strategies to generate very large numbers of transplantable cells (e.g., by differentiating induced pluripotent stem cells), limitations directly linked to the interaction between transplanted cells and the host will continue to hamper a successful outcome. Among these limitations, host inflammatory and immune responses challenge the critical phases after cell delivery, including engraftment, migration, and differentiation. Therefore, it is key to study the mechanisms and dynamics that impair the efficacy of cell transplants in order to develop strategies that can ultimately improve the outcome of allogeneic and autologous stem cell therapies, in particular for severe disease such as muscular dystrophies. In this review we provide an overview of the main players and issues involved in this process and discuss potential approaches that might be beneficial for future regenerative therapies of skeletal muscle.
    BioMed Research International 06/2014; 2014(4):964010. DOI:10.1155/2014/964010 · 2.71 Impact Factor
  • Source
    • "j o u r n a l ho m e p a g e : w w w . e l s e v i e r. c o m / l oc a t e / t o x i c o n production by myoblasts (Boyd et al., 2006; Frost et al., 2006; Lang et al., 2003). Moreover, evidences from in vitro and in vivo studies also showed that lipopolysaccharide (LPS), a specific TLR4 ligand, activates the classical NFkB pathway in muscle cells leading to the production of TNFa, IL-1b, and IL-6 proinflammatory cytokines (Frost and Lang, 2008; Frost et al., 2004; Marino et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune cells and skeletal muscle express Toll-like receptors (TLRs) that participate as sensors of tissue injury triggering signals for activation of innate and adaptive immune responses. This study aimed to investigate the involvement of TLR4 in the process of skeletal muscle repair. Muscular injury was induced by injection of 0,6 mg/kg of Bothrops jararacussu snake venom in the gastrocnemius muscle of C3H/HeJ mice that express a non-functional TLR-4 receptor and C3H/HeN mice with functional receptor. TLR4-deficient mice had persistent muscular inflammation with few F4/80 macrophages at onset but increased MMP-9 activity and collagen deposition during resolution of injury. Since such effect was not observed in the mouse strain with functional receptor it is concluded that TLR4 signaling exerts a protective role preventing from excessive muscular damage induced by Bothrops jararacussu venom.
    Toxicon 10/2012; 60(8). DOI:10.1016/j.toxicon.2012.10.003 · 2.58 Impact Factor
  • Source
    • "Emerging data indicates that TLR signaling may also underlie the development of chronic inflammation and insulin resistance in skeletal muscle. Skeletal muscle cells and intact whole muscle express multiple TLRs, including TLR2 and TLR4 [101], that are responsive to LPS [102]. Moreover, skeletal muscle TLR4 gene and protein expression are significantly elevated in muscle from obese subjects with type 2 diabetes [103]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.
    Gastroenterology Research and Practice 08/2010; 2010(1687-6121). DOI:10.1155/2010/212563 · 1.75 Impact Factor
Show more