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

Nat Commun. 2015 Jun 2;6:7216. doi: 10.1038/ncomms8216.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / immunology
  • CD4-Positive T-Lymphocytes
  • Cell Differentiation / immunology
  • Chromatin Immunoprecipitation
  • Cyclic AMP Response Element-Binding Protein / immunology*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dinoprostone / pharmacology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • HEK293 Cells
  • Humans
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Promoter Regions, Genetic
  • Real-Time Polymerase Chain Reaction
  • Spinal Cord / immunology
  • Th17 Cells / immunology*
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Transcription Factors / immunology*

Substances

  • Creb1 protein, mouse
  • Crtc2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Il17a protein, mouse
  • Il17f protein, mouse
  • Interleukin-17
  • Transcription Factors
  • Dinoprostone