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 7

In vivo EP4 antagonist treatment decreases autoimmune pathology.

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In vivo EP4 antagonist treatment decreases autoimmune pathology. (A) NOD...
(A) NOD mice treated with grapiprant (EP4 antagonist) or untreated (control) for 4 weeks were then injected with cell tracer dye–labeled transgenic BDC2.5 CD4 T cells, and cell proliferation was checked 6 days after transfer. Cell division was compared between EP4 antagonist–treated and untreated control mice by counting cell numbers for each division. (B) Separate group of control or EP4-inhibited mice (did not received BDC2.5 CD4 T cells) were checked for islet lymphocyte infiltration (6 weeks after treatment). Pancreas tissue samples were sectioned for H&E staining, and islet infiltration was ranked as follows: no infiltration, 0; 10%–20%, 1; 20%–50%, 2; and >50%, 3. Data are presented with average score or number of islets with different levels of infiltration with lymphocytes. Data are representative of 2 independent experiments (A and B). Each experiment was performed with 3–4 mice per group. The graph shows mean ± SD for each of the experiments. Statistical analysis was performed with 1-way ANOVA with Bonferroni post-test. (C) Proposed schematic model of altered balance of IL-R/IL-1 and IFNAR signaling in adult prediabetic NOD mice with modulation by PGE2-EP4 and NLRP3, and reestablishment of homeostatic balance after inhibiting EP4 signals. Prediabetic NOD mice showed increased expression of IL1, PGE2, PTGER4, and NLRP3 (red). PGE2-EP4 were key regulators of enhancing NLRP3 and IL1 that was inhibitory to IFNAR signaling (bold lines). After inhibition of EP4, IFNAR signaling increased by reducing IL1.