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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 3

Inflammatory signature identified in NOD APCs correlates with increased PTGER4 and PGE2.

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Inflammatory signature identified in NOD APCs correlates with increased ...
(A) Z scores for IPA signaling pathways significantly altered in moDCs and cDC2 from NOD versus B6.g7 mice. (B) Bubble plots of key inflammatory gene sets from GSEA of NOD APCs compared with B6.g7 APCs using the immunologic signatures gene sets from MSigDB. Gene sets enriched with genes with lower expression in NOD mice compared with B6.g7 mice are depicted as blue circles, while gene sets with higher expression in NOD mice are depicted as red circles. Circle size indicates FDR-adjusted P values, and color intensity indicates normalized enrichment scores. (C) Hierarchical clustering of significant IPA upstream regulators with increased expression in NOD mice as ranked by Z score, which indicates the predicted enrichment in NOD mice compared with B6.g7 mice. (D) Gene expression measured by qPCR for IL-1β, Nlrp3, and Ptger4 after 4 hours of LPS stimulation of spleen cells from 8-week-old prediabetic NOD and B6.g7 mice. Plots are representative of 2 independent experiments with 3 mice per group. (E) PGE2 levels in sera from NOD and B6.g7 mice (representative of 2 experiments, 3 mice per group) at weeks 3 and 8. Comparison was made between NOD and B6.g7 mice; P values were calculated using t test. Data show mean ± SD. (F and G) Protein expression level by Western blot of PTGER4 and PTGER2 in bone marrow–derived DCs from NOD and B6.g7 mice, from 0–4 hours after LPS (500 ng/ml) stimulation. Relative quantification of bands normalization to HSP90 is indicated underneath. *P < 0.05, **P < 0.01.

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