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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Jeniffer B. Hernandez & Christina Chang & Mathias LeBlanc & David Grimm & John Le Lay & Klaus H. Kaestner & Ye Zheng & Marc Montminy, 2015. "The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8216
    DOI: 10.1038/ncomms8216
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