The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation

Jeniffer B. Hernandez, Christina Chang, Mathias LeBlanc, David Grimm, John Le Lay, Klaus H. Kaestner, Ye Zheng and Marc Montminy ()
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Jeniffer B. Hernandez: Peptide Biology Laboratories, Salk Institute
Christina Chang: Nomis Foundation for Immunobiology and Microbial Pathogenesis Laboratories, Salk Institute
Mathias LeBlanc: Peptide Biology Laboratories, Salk Institute
David Grimm: Peptide Biology Laboratories, Salk Institute
John Le Lay: Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine
Klaus H. Kaestner: Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine
Ye Zheng: Nomis Foundation for Immunobiology and Microbial Pathogenesis Laboratories, Salk Institute
Marc Montminy: Peptide Biology Laboratories, Salk Institute

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: Abstract Following their activation in response to inflammatory signals, innate immune cells secrete T-cell-polarizing cytokines that promote the differentiation of naive CD4 T cells into T helper (Th) cell subsets. Among these, Th17 cells play a prominent role in the development of a number of autoimmune diseases. Although regarded primarily as an immunosuppressant signal, cAMP has been found to mediate pro-inflammatory effects of macrophage-derived prostaglandin E2 (PGE2) on Th17 cells. Here we show that PGE2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2. Following its dephosphorylation, CRTC2 stimulates the expression of the cytokines IL-17A and IL-17F by binding to CREB over both promoters. CRTC2-mutant mice have decreased Th17 cell numbers, and they are protected from experimental autoimmune encephalitis, a model for multiple sclerosis. Our results suggest that small molecule inhibitors of CRTC2 may provide therapeutic benefit to individuals with autoimmune disease.

Date: 2015
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DOI: 10.1038/ncomms8216

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