Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
Year: 2020
Type: article
Abstract: Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect. Moreover, curdlan, a PRR-dependent microbial product, activates CREB and represses IRF4 and KLF4, resulting in a pro-Th17 phenotype of cDC2s. These in vitro and in vivo results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the classification of novel cDC2 and cDC17 subsets. The findings also reveal that repressing IRF4 and KLF4 pathway can be harnessed for immuno-regulation.
Source: eLife
DOI: 10.7554/elife.49416
Institutions: University of California San Diego, Second Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Dankook University, Instituto de Salud Carlos III, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), University of Tübingen, Boston University, VA Boston Healthcare System, University of California, Davis, VA San Diego Healthcare System
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: U.S. Department of Veterans Affairs, Crohn's and Colitis Foundation of America, Crohn's and Colitis Foundation, UCSD-UCLA Diabetes Research Center, Deutsche Forschungsgemeinschaft, National Natural Science Foundation of China, National Institutes of Health, University of California, San Diego, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1130592683, Chromosome 17q21, allergic inflammation, and remodeling, G1340632512, G1462415530, GSDMB and mucosal allergic response, G2132089205, Role of IRF4 in T helper cell fate decisions, G2302452045, G2322290807, G2637320451, G2884968204, G3036248164, A novel pathway of Th17/Th2 induction: The role of cAMP signaling in DC, Center for Reproductive Science and Medicine, G3304255626, G3323803443, G3360784914, G356969442, G4491251053, G4713889301, G5478218612, G6331392353, G6498739133, G654586262, Center for Reproductive Science and Medicine, G6864671671, G7386523713, Specialized Cancer Center Support Grant, Control of mucosal immunity by Gas- vs Gai-linked GPCR signaling in dendritic cells, G9000021148, G9000034789, G9000076902, G9000140433, Time-restricted feeding and breast cancer, Diabetes Research Center (DRC), Experimental Endocrinology and Metabolism, Airway Inflammation and Airway Remodeling in Severe Asthma, G956705925
OpenAlex ID: W3004479054