The myeloid IL-1 receptor limits IL-27–mediated endothelial type I IFN during nephrotoxic serum nephritis
6 affiliations
- 1Department of Anesthesiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
- 2Department of Anesthesiology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, China.
- 3Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
- 4Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan.
- 5Durham VA Medical Center, Durham, North Carolina, USA.
- 6Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
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, hereafter 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 1 (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.
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BibTeX
@article{chen2026myeloid,
title = {{The myeloid IL-1 receptor limits IL-27–mediated endothelial type I IFN during nephrotoxic serum nephritis}},
author = {Yanting Chen and Yu Li and Jiafa Ren and Chia-Chun Wu and Xiaohan Lu and Achintya Inumarty and Steven D. Crowley and Jamie R. Privratsky},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.200728},
url = {https://doi.org/10.1172/jci.insight.200728},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The myeloid IL-1 receptor limits IL-27–mediated endothelial type I IFN during nephrotoxic serum nephritis
AU - Yanting Chen
AU - Yu Li
AU - Jiafa Ren
AU - Chia-Chun Wu
AU - Xiaohan Lu
AU - Achintya Inumarty
AU - Steven D. Crowley
AU - Jamie R. Privratsky
PY - 2026
DA - 2026/09/01
JO - JCI Insight
DO - 10.1172/jci.insight.200728
UR - https://doi.org/10.1172/jci.insight.200728
AB - 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, hereafter 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 1 (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.
SN - 2379-3708
ER -