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


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hernandez, JB; Chang, C; LeBlanc, M; Grimm, D; Le Lay, J; Kaestner, KH; Zheng, Y; Montminy, M

Published Date

  • June 2, 2015

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 7216 -

PubMed ID

  • 26031354

Pubmed Central ID

  • 26031354

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms8216


  • eng