The Contribution of Muscle Innate Immunity to Uremic Cachexia

Protein energy wasting (PEW) is a common complication both in chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Of note, PEW is one of the stronger predictors of morbidity and mortality in this patient population. The pathogenesis of PEW involves several mechanisms, including anorexia, insulin resistance, acidosis and low-grade inflammation. In addition, sterile muscle inflammation contributes to PEW at an advanced CKD stage. Both immune and resident muscle cells can activate innate immunity; thus, they have critical roles in triggering sterile tissue inflammation. Toll-like receptor 4 (TLR4) can detect endogenous danger-associated molecular patterns generated or retained in blood in uremia and induce a sterile muscle inflammatory response via NF-& kappa;B in myocytes. In addition, TLR4, though the activation of the NLRP3 inflammasome, links the sensing of metabolic uremic stress in muscle to the activation of pro-inflammatory cascades, which lead to the production of IL-1 & beta; and IL-18. Finally, uremia-induced accelerated cell senescence is associated with a secretory phenotype that favors fibrosis in muscle. Targeting these innate immune pathways could lead to novel therapies for CKD-related PEW.

Automated summary

Protein energy wasting (PEW) is a common complication in chronic kidney disease (CKD) and end-stage kidney disease (ESKD), and it is strongly associated with morbidity and mortality in these patient populations. The pathogenesis of PEW involves various mechanisms such as anorexia, insulin resistance, acidosis, low-grade inflammation, and sterile muscle inflammation at advanced CKD stages. Immune and resident muscle cells play critical roles in triggering sterile tissue inflammation through innate immunity pathways, including toll-like receptor 4 (TLR4) activation and NLRP3 inflammasome signaling. Targeting these innate immune pathways could potentially lead to novel therapies for CKD-related PEW.