Toll‐like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease

Abstract

BackgroundInflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up‐regulates pro‐inflammatory cytokines is unknown. Toll‐like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro‐inflammatory cytokine.MethodsTLR4, phospho‐p65, phospho‐ikBα, tumour necrosis factor (TNF)‐α, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (n = 29) and controls (n = 14) by immunohistochemistry, western blot, and RT–PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT–PCR) and TLR‐driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot.ResultsCKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB‐regulated gene TNF‐α was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF‐α and down‐regulated pAkt. These effects were prevented by blockade of TLR4.ConclusionsCKD promotes muscle inflammation through an up‐regulation of TLR4, which may activate downward inflammatory signals such as TNF‐α and NFkB‐regulated genes.

Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway

“…Here, IL-1β application induced a translocation of the p65, p50, and c-rel NF-ĸB subunits into the nucleus [52]. Similarly, in patients suffering from chronic kidney disease, increased muscle inflammation has been associated with increased NF-ĸB expression [53]. Summarized, these findings clearly indicate at the therapeutical relevance of both, the pro-inflammatory IL-1β as well as NF-kB inhibition in inflammatory conditions.…”

Muscle wasting and sarcopenia in heart failure: a brief overview of the current literature

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“…Chronic kidney disease promotes muscle inflammation through an up-regulation of toll-like receptor 4, which may activate downward inflammatory signals such as tumour necrosis factor and nuclear factor κB-regulated genes. 65 Like in HF, it has been difficult to suppress muscle wasting in patients with CKD. In vitro and in vivo models have used, for example, dexamethasone administration as well as ursolic acid derived from plants.…”

Contemporary publication patterns in the Journal of Cachexia, Sarcopenia and Muscle by type and sub‐speciality: facts and numbers

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