Interleukin-1β Activates a MYC-Dependent Metabolic Switch in Kidney Stromal Cells Necessary for Progressive Tubulointerstitial Fibrosis

Abstract

<b>Background</b> Kidney injury is characterized by persisting inflammation and fibrosis, yet mechanisms by which inflammatory signals drive fibrogenesis remain poorly defined.<b>Methods</b> RNA sequencing of fibrotic kidneys from patients with CKD identified a metabolic gene signature comprising loss of mitochondrial and oxidative phosphorylation gene expression with a concomitant increase in regulators and enzymes of glycolysis under the control of PGC1<i>α</i> and MYC transcription factors, respectively. We modeled this metabolic switch <i>in vivo</i>, in experimental murine models of kidney injury, and <i>in vitro</i> in human kidney stromal cells (SCs) and human kidney organoids.<b>Results</b> In mice, MYC and the target genes thereof became activated in resident SCs early after kidney injury, suggesting that acute innate immune signals regulate this transcriptional switch. <i>In vitro</i>, stimulation of purified human kidney SCs and human kidney organoids with IL-1<i>β</i> recapitulated the molecular events observed <i>in vivo</i>, inducing functional metabolic derangement characterized by increased MYC-dependent glycolysis, the latter proving necessary to drive proliferation and matrix production. MYC interacted directly with sequestosome 1/p62, which is involved in proteasomal degradation, and modulation of p62 expression caused inverse effects on MYC expression. IL-1<i>β</i> stimulated autophagy flux, causing degradation of p62 and accumulation of MYC. Inhibition of the IL-1R signal transducer kinase IRAK4 <i>in vivo</i> or inhibition of MYC <i>in vivo</i> as well as in human kidney organoids <i>in vitro</i> abrogated fibrosis and reduced tubular injury.<b>Conclusions</b> Our findings define a connection between IL-1<i>β</i> and metabolic switch in fibrosis initiation and progression and highlight IL-1<i>β</i> and MYC as potential therapeutic targets in tubulointerstitial diseases.