The Contribution of Muscle Innate Immunity to Uremic Cachexia

Author:

Esposito Pasquale12ORCID,Verzola Daniela2,Saio Michela1,Picciotto Daniela1,Frascio Marco34,Laudon Alessandro5,Zanetti Valentina12,Brunori Giuliano5,Garibotto Giacomo2ORCID,Viazzi Francesca12ORCID

Affiliation:

1. Division of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy

2. Department of Internal Medicine, University of Genova, 16132 Genova, Italy

3. Division of Surgery, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy

4. Department of Surgical Sciences and Integrated Diagnostics, University of Genova, 16132 Genova, Italy

5. Division of Nephrology, Ospedale Santa Chiara, 38122 Trento, Italy

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.

Funder

University of Genoa

Publisher

MDPI AG

Subject

Food Science,Nutrition and Dietetics

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