A Toll‐like receptor‐4/NLRP3 inflammasome pathway promotes inflammation in skeletal muscle of chronic kidney disease patients

Abstract Background An emerging hypothesis is that the activation of innate immunity in the muscle of patients with chronic kidney disease (CKD) is implicated in the development and progression of wasting and cachexia. We previously observed that Toll‐like receptor‐4 (TLR4) and its downward NF‐κB‐dependent pro‐inflammatory pathways are activated in CKD muscle. It is however unknown if TLR4 can activate the TLR4/NOD, LRR, and pyrin domain‐containing protein 3 (NLRP3) inflammasome pathway, which is implicated in cardiovascular disease and frailty, clinical settings that are commonly observed in CKD patients. Methods In a case–control cohort study, we hypothesized that a TLR4/NLRP3 inflammasome pathway is activated in skeletal muscle in uraemia. First, we studied the regulation TLR4/NLRP3/caspase‐1 in skeletal muscle biopsies (20M/11F) obtained from 31 non‐diabetic CKD5 patients (eGFR 8 ± 1 mL/min 1.73 m2) scheduled for peritoneal dialysis catheter insertion and 15 controls (10M/5F, eGFR 99 ± 6 mL/min 1.73 m2). Second, the effects of uraemic serum on the TLR4/NLRP3 inflammasome pathway were studied in C2C12 cells. Results In the muscle of CKD subjects, NLRP3 mRNA as well as its protein were overexpressed (by ~16‐fold, respectively, P