An Uromodulin mutation drives autoimmunity and kidney mononuclear phagocyte endoplasmic reticulum stress.

An Uromodulin mutation drives autoimmunity and kidney mononuclear phagocyte endoplasmic reticulum stress. Am J Pathol. 2020 Sep 11;: Authors: Plotkin M, O'Brien CA, Goellner J, Williams J, Carter W, Sharma S, Stone A Abstract We identified a family with a UMOD gene mutation (C106F) resulting in glomerular inflammation and complement deposition. To determine if the observed phenotype is due to immune system activation by mutant uromodulin, we developed a mouse line with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene using CRISPR-Cas9 gene editing and examined the effect of this mutation on mononuclear phagocytic cells. Mutant mice develop high levels of intracellular and secreted aggregated uromodulin resulting in anti-uromodulin antibodies and circulating uromodulin containing immune complexes with glomerular deposition and kidney fibrosis with aging. F4/80+ and CD11c+ kidney cells phagocytize uromodulin. Differential gene expression analysis by RNA sequencing of F4/80+ phagocytic cells revealed activation of the ATF5 mediated stress response pathway in mutant mice. Phagocytosis of mutant uromodulin by cultured dendritic cells resulted in activation of the ER stress response pathway and markers of cell inactivation, an effect not seen with WT protein. Mutant mice demonstrate a 2-fold increase in Treg cells, consistent with induction of immune tolerance resulting in decreased inflammatory response and improve...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research