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Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice
M. Jubayer Rahman, … , Timothy W. Thoner, Kristin V. Tarbell
M. Jubayer Rahman, … , Timothy W. Thoner, Kristin V. Tarbell
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e97843. https://doi.org/10.1172/jci.insight.97843.
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Research Article Inflammation

Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice

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Abstract

Type I IFN (IFN-I) dysregulation contributes to type 1 diabetes (T1D) development, and although increased IFN-I signals are pathogenic at the initiation of autoimmune diabetes, IFN-I dysregulation at later pathogenic stages more relevant for therapeutic intervention is not well understood. We discovered that 5 key antigen-presenting cell subsets from adult prediabetic NOD mice have reduced responsiveness to IFN-I that is dominated by a decrease in the tonic-sensitive subset of IFN-I response genes. Blockade of IFNAR1 in prediabetic NOD mice accelerated diabetes and increased Th1 responses. Therefore, IFN-I responses shift from pathogenic to protective as autoimmunity progresses, consistent with chronic IFN-I exposure. In contrast, IL-1–associated inflammatory pathways were elevated in prediabetic mice. These changes correlated with human T1D onset-associated gene expression. Prostaglandin E2 (PGE2) and prostaglandin receptor 4 (PTGER4), a receptor for PGE2 that mediates both inflammatory and regulatory eicosanoid signaling, were higher in NOD mice and drive innate immune dysregulation. Treating prediabetic NOD mice with a PTGER4 antagonist restored IFNAR signaling, decreased IL-1 signaling, and decreased infiltration of leukocytes into the islets. Therefore, innate cytokine alterations contribute to both T1D-associated inflammation and autoimmune pathogenesis. Modulating innate immune balance via signals such as PTGER4 may contribute to treatments for autoimmunity.

Authors

M. Jubayer Rahman, Kameron B. Rodrigues, Juan A. Quiel, Yi Liu, Vipul Bhargava, Yongge Zhao, Chie Hotta-Iwamura, Han-Yu Shih, Annie W. Lau-Kilby, Allison M.W. Malloy, Timothy W. Thoner, Kristin V. Tarbell

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Figure 4

Genes differentially expressed in NOD APCs correlate with IL-1–dependent gene signatures from new-onset human T1D.

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Genes differentially expressed in NOD APCs correlate with IL-1–dependent...
GSEA for NOD DE genes with 2 human data sets. (A) Enrichment results from Chen et al. (41) showing genes DE lower (n = 282) or higher (n = 175) in patients with recent-onset type 1 diabetes positively correlate with DE genes from NOD APCs. (B) Enrichment results from Cabrera et al. (21) showing that genes expressed at lower (n = 368) or higher levels (n = 160) with IL-1R antagonist treatment of individuals with new-onset T1D negatively correlate with DE genes from NOD APCs. NES, normalized enrichment statistic. Nominal estimated P values determined using GSEA software.

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