The Contribution of Muscle Innate Immunity to Uremic Cachexia

Abstract

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-κB 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-1β 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.

Keywords: CKD; amino acids; innate immunity; muscle; protein metabolism.

Figure 1

The innate immune response in skeletal muscle. Skeletal muscle has an afferent sensory limb containing, among others, receptors for immune modulators, such as Toll-like receptor (TLR) agonists, damage/pathogen-associated molecular patterns (D/PAMPs), cytokines and chemokines (IL, IFN and TNF) and growth factors and hormones (e.g., insulin, growth hormone, catecholamines, etc.). Upon TLR activation, muscles respond by activating NF-κB and other transcription factors to produce and release innate immune factors (efferent limb). The muscle innate immune response to pathogens and DAMPs can exert profound effects on muscle protein metabolism due to an imbalance between protein synthesis and an increase in rates of protein degradation, mediated by up-regulation of the ubiquitin–proteasome, autophagy or calpain. In addition, inflammatory cytokines cause resistance to anabolic signals by antagonizing the actions of anabolic hormones and exercise-induced signals. While an increased release of amino acids from skeletal muscle is of major benefit to support glucose and acute-phase protein synthesis, on a long-term basis, the inflammatory response is followed by cachexia and has been associated with worse outcomes. Abbreviations used in the figure are defined in the text. Modified from: R. A. Frost, C. H. Lang Regulation of muscle growth by pathogen-associated molecules. J. Anim. Sci. 2008, 86, E84–E93 [28].

Figure 2

A two-phase process, with an inception and an activation step, leads to the activation of NLRP3 inflammasome. During the inception phase, TLRs or TNF activate nuclear factor kappa-B (NF-κB), up-regulating NLRP3 and IL-1β proteins. During the activation phase, several DAMPs (including uric acid, cholesterol and amyloid β-protein) induce NLRP3 inflammasome assembly and subsequent activation. Following its activation, NLRP3 recruits the adaptor protein ASC through PYD–PYD interactions, polymerizing ASC. Pro-caspase-1 is recruited by ASC and undergoes auto-cleavage into caspase-1, causing the maturation of IL-1β and IL-18 and triggering an immune response. Abbreviations are defined in the text.

Figure 3

(A,B). Relationships between muscle NLRP3 mRNA (A), logIL-1 β protein (B) and estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease. IL-1β, interleukin-1β; NLRP3, NOD, LRR and pyrin-domain-containing protein 3 (Reprinted from Ref. [50]. Verzola D.; et al. JCSM Rapid Commun. 2023, 6, 50–61. Published online in Wiley Online Library (wileyonlinelibrary.com) https://doi:10.1002/rco2.75. CC-BY-NC license).