Fibrosis and persistent inflammation are characteristics of kidney injury, but the molecular mechanisms of the crosstalk between them are unclear. Now, Lemos et al. report that in acute kidney injury (AKI), the innate immune pro-inflammatory cytokine IL-1β induces a metabolic switch in platelet-derived growth factor receptor (PDGFRβ)+ kidney stromal cells (SCs), which promotes tubulointerstitial fibrosis.
RNA sequencing of healthy kidney or chronic kidney disease (CKD) biopsy samples revealed a switch in metabolic gene expression from oxidative phosphorylation (OXPHOS) in healthy kidney tissue to glycolysis in fibrotic renal tissue. Furthermore, the expression of the transcription regulator MYC and its coactivator MAZ were upregulated, whereas that of the mitochondrial biogenesis regulator PPARGC1A was downregulated in CKD. Additionally, MYC protein levels were substantially elevated in the interstitial cells in CKD biopsy samples, whereas MYC was almost undetectable in healthy kidney tissue. Examination of metabolic gene expression in mouse kidney SCs and fibrogenic myofibroblasts in the unilateral ureteral obstruction (UUO) model of renal fibrosis confirmed that this OXPHOS–glycolysis switch during the transition from AKI to CKD occurred in vivo.
Next, the researchers analysed the translatome of tubulointerstitial SCs in injured mouse kidneys and found that the expression of IL-1β and MYC was significantly correlated, and the expression of downstream genes in the IL-1 receptor signalling pathway was upregulated by AKI. Stimulating primary human SCs in vitro with IL-1β resulted in the upregulation of MYC and its target glycolytic proteins, which was blocked by an inhibitor of IL-1 receptor-associated kinase 4 (IRAK4). Furthermore, in a mouse model of ischaemia–reperfusion injury (IRI)-induced kidney injury, the IRAK4 inhibitor blocked the upregulation of MYC and reduced the proliferation of SCs after IRI. Additionally, IL-1β treatment induced a metabolic switch and increased proliferation of primary human SCs in vitro, which was blocked by a MYC inhibitor. Thus, an IL-1 receptor–IRAK4–MYC axis regulates kidney SC proliferation and metabolism.
IL-1 receptor signalling is known to activate autophagy and, indeed, IL-1β induced autophagosome formation and increased degradation of the cargo protein p62 in primary human SCs in vitro. Additionally, autophagy gene expression was higher in severely fibrotic human kidney tissue than in healthy kidney tissue. As p62 recognizes polyubiquitylated proteins to mediate their proteasomal degradation, MYC might be a direct target of p62. Deletion of the gene encoding p62 in human kidney SCs by CRISPR–Cas9 increased the levels of MYC and its target genes, whereas overexpression of p62 reduced MYC levels. Moreover, p62 and MYC interact and MYC appears to be polyubiquitylated in p62-deficient cells treated with a proteasome inhibitor. Thus, it is likely that MYC is a direct target of p62.
To examine the effects of modulating the IL-1 receptor–IRAK4–MYC axis in vivo, the researchers treated UUO mice with an inhibitor of MYC expression during the inflammatory phase of AKI. Interestingly, not only was SC proliferation reduced during AKI, but the number of myofibroblasts, the expression of collagen genes and collagen deposition in the tubulointerstitium (all indicative of fibrosis) were also reduced by the MYC expression inhibitor. The researchers next switched to using 3D human kidney organoids. “We could study multiple tissue events triggered by IL-1β alone. This ‘single cytokine’ approach was possible because organoids lack haematopoietic innate immune cells,” Dario Lemos explains. IL-1β stimulation induced hypertrophy of kidney organoids, proximal tubule cell atrophy and increased expression of kidney injury molecule 1, all indicators of proximal tubular damage. Additionally, increased expression of collagen genes and interstitial collagen deposition suggested that fibrosis also occurred in response to IL-1β treatment. Importantly, these effects were blocked by inhibition of MYC expression. Thus, IL-1β can drive tubulointerstitial disease by inducing proximal tubule damage and fibrosis.
“IL-1β can drive tubulointerstitial disease by inducing proximal tubule damage and fibrosis”
“IL-1β induces an inflammatory metabolic phenotype in fibrogenic kidney SCs, which resembles the immunometabolism of monocytes and macrophages,” explains Lemos. “Therefore, we should think of kidney SCs not just as extracellular matrix-producing cells, but also as cells that actively contribute to local inflammation.”
Lemos, D. R. et al. Interleukin-1β activates a MYC-dependent metabolic switch in kidney stromal cells necessary for progressive tubulointerstitial fibrosis. J. Am. Soc. Nephrol. https://doi.org/10.1681/ASN.2017121283 (2018)
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Otto, G. IL-1β switches on kidney fibrosis. Nat Rev Nephrol 14, 475 (2018). https://doi.org/10.1038/s41581-018-0026-2
Scientific Reports (2020)