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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Categories: Research Article Inflammation

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

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 6

In vivo PTGER4 antagonist treatment increases IFNAR signaling but decreases IL-1 and IFN-γ.

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In vivo PTGER4 antagonist treatment increases IFNAR signaling but decrea...
(A) Total splenocytes from NOD mice treated with PTGER4 antagonist or anti–IL-1R as indicated were stimulated with IFN-α for 2 hours, and IFN-I–response gene expression was determined by qPCR. (B) IFN-α–stimulated STAT1 nuclear localization. Spleen cells from untreated or treated (PTGER4 antagonist/anti-IL1R-antibody) NOD mice were stimulated with IFN-α for 30 minutes, and nuclear STAT1 localization was determined by confocal microscopy, as in Supplemental Figure 1B. Images (15/slide) were quantified to determine the percentage of CD11c+ cells positive for nuclear STAT1 and the intensity of STAT1 levels within CD11C+ population. (C) IFN-γ transcripts were measured in mixed cells prepared from spleen or pancreatic lymph nodes, 4 weeks after treatment with or without PTGER4 antagonist. (D) Four weeks after treatment with or without PTGER4 antagonist, CD11c+ cells were enriched from the spleen, and IL-1 protein levels were detected by Western blotting. Protein bands were quantified relative to HSP90 (lysate) or total cell number (supernatant). Data are representative of at least 2 independent experiments performed with 3 individual mice per group (A and C) or pooled from 3 mice (B and D), mean ± SD for each of the experiments (A–C). Statistical analysis was performed with 1-way ANOVA with Bonferroni post-test. *P < 0.05, **P < 0.01.