Year: 2015
Type: article
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. Multiple sclerosis is caused by autoreactive Th17 lymphocytes. Here the authors show that prostaglandin E2 promotes Th17 differentiation by activating transcription of IL-17 by CREB/CRTC2 complex, and that ablation of CRTC2 prevents Th17 differentiation and multiple sclerosis in a mouse model.
Source: Nature Communications
DOI: 10.1038/ncomms8216
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Multiple Sclerosis Society, Rita Allen Foundation, Leona M. and Harry B. Helmsley Charitable Trust, Multiple Sclerosis Society, Fondation pour la Recherche Médicale, NOMIS Stiftung, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
OpenAlex ID: W614921467