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

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

Author information

1
Peptide Biology Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
2
Nomis Foundation for Immunobiology and Microbial Pathogenesis Laboratories, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
3
Department of Genetics, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-5156, USA.

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.

PMID:
26031354
PMCID:
PMC4545657
DOI:
10.1038/ncomms8216
[Indexed for MEDLINE]
Free PMC Article

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