Interleukin-1ß Activates a MYC-Dependent Metabolic Switch in Kidney Stromal
Cells Necessary for Progressive Tubulointerstitial Fibrosis.
Authors Lemos DR, McMurdo M, Karaca G, Wilflingseder J, Leaf IA, Gupta N, Miyoshi T,
Susa K, Johnson BG, Soliman K, Wang G, Morizane R, Bonventre JV, Duffield JS
Submitted By Ryuji Morizane on 5/13/2019
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2018
Date Published
Volume : Pages 29 : 1690 - 1705
PubMed Reference 29739813
Abstract Background Kidney injury is characterized by persisting inflammation and
fibrosis, yet mechanisms by which inflammatory signals drive fibrogenesis remain
poorly defined.Methods 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 PGC1a and MYC
transcription factors, respectively. We modeled this metabolic switch in vivo,
in experimental murine models of kidney injury, and in vitro in human kidney
stromal cells (SCs) and human kidney organoids.Results 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. In vitro, stimulation of purified human kidney SCs and human kidney
organoids with IL-1ß recapitulated the molecular events observed in vivo,
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-1ß stimulated autophagy flux, causing
degradation of p62 and accumulation of MYC. Inhibition of the IL-1R signal
transducer kinase IRAK4 in vivo or inhibition of MYC in vivo as well as in human
kidney organoids in vitro abrogated fibrosis and reduced tubular
injury.Conclusions Our findings define a connection between IL-1ß and metabolic
switch in fibrosis initiation and progression and highlight IL-1ß and MYC as
potential therapeutic targets in tubulointerstitial diseases.

Investigators with authorship
Ryuji MorizaneBrigham and Womens Hospital