Abstract
Autoimmune kidney diseases can cause glomerulonephritis and tubulointerstitial nephritis, which if unresolved, lead to progressive glomerulosclerosis and tubulointerstitial fibrosis. The IL-1 receptor (IL-1R1) is known to have divergent and cell-specific effects in kidney injury. We hypothesized that IL-1R1 would dampen pro-inflammatory activation of myeloid cells such that deletion of myeloid cell IL-1R1 would exacerbate autoimmune nephritis. Mice with myeloid cell-specific deletion of IL-1R1 (LysMCre(+) / Il1r1fl/fl - MKO) and littermate controls (LysMCre(-) / Il1r1fl/fl - MWT) were subjected to nephrotoxic serum (NTS) nephritis. MKO mice demonstrated worsened glomerular and tubular injury as indicated by increased albuminuria, glomerular injury scores, and kidney mRNA levels of kidney injury molecule (KIM)-1 (Havcr1) and neutrophil gelatinase-associated lipocalin (NGAL/Lcn2). We further found that myeloid IL-1R1 deficiency resulted in increased myeloid cell ER stress and expression of the heterodimeric cytokine Ebi3/Il27a (IL-27). IL-27 then induced increased type I IFN expression by kidney endothelial cells. In turn, anti-IL-27 limited type I IFN expression in endothelial cells and NTS nephritis, and anti-IFNAR1 therapy ameliorated glomerular and tubular injury in MKO mice. Thus, we demonstrated a myeloid cell-endothelial cell immunoregulatory axis whereby myeloid IL-1R1 activity constrained endothelial type I IFN generation to limit chronic kidney damage.
Authors
Yanting Chen, Yu Li, Jiafa Ren, Chia-Chun Wu, Xiaohan Lu, Achintya Inumarty, Steven D. Crowley, Jamie R. Privratsky
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