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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 2

Lower IFN response genes correlate with diabetes pathogenesis, and blocking IFNAR in prediabetic NOD mice accelerates diabetes and increases Th1 responses.

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Lower IFN response genes correlate with diabetes pathogenesis, and block...
(A) Type I IFN gene expression in sorted splenic moDCs from age-matched NOD and B6.g7 mice. (B) NOD mice were treated i.p. with anti-IFNAR1 antibody or control monoclonal antibody 2 times/week from 6–8 weeks of age. The percentage of diabetes-free mice was recorded and compared between the anti–IFNAR antibody–treated group and untreated control group. Statistical analysis was performed with log-rank test. Summation of 2 experiments with n = 16 mice (C) Intracellular IFN-γ staining in lymph node–derived CD4+ T cells, after PMA plus ionomycin (Ion) stimulation (total 6 hours), where brefeldin A was added for the last 4 hours. (D) Counts of intracellular CD4+IFN-γ+ T cells in lymph node after PMA plus Ion stimulation. Data were pooled from 2 independent experiments, with 5–6 mice per group (A, C, and D). Values show individual mice, with mean ± SD. P values in A, C and D were calculated using t test. *P < 0.05, **P < 0.01.

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