Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
Por:
Lee J, Zhang J, Chung YJ, Kim JH, Kook CM, Gonzalez J, Herdman DS, Nürnberg B, Insel PA, Corr M, Mo JH, Tao A, Yasuda K, Rifkin IR, Broide DH, Sciammas R, Webster NJ and Raz E
Publicada:
4 feb 2020
Resumen:
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.
Filiaciones:
Lee J:
Department of Medicine, University of California San Diego, San Diego, United States
Zhang J:
Department of Medicine, University of California San Diego, San Diego, United States
The Second Affiliated Hospital of Guangzhou Medical University (GMU), The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou, China
Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
Chung YJ:
Department of Medicine, University of California San Diego, San Diego, United States
Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University College of Medicine, Chungnam, Republic of Korea
Kim JH:
Department of Medicine, University of California San Diego, San Diego, United States
Kook CM:
Department of Medicine, University of California San Diego, San Diego, United States
Gonzalez J:
Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
Alicante Institute for Health and Biomedical Research (ISABIAL - FISABIO), Alicante, Spain
Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, Madrid, Spain
Herdman DS:
Department of Medicine, University of California San Diego, San Diego, United States
Nürnberg B:
Department of Pharmacology and Experimental Therapy, University of Tübingen, Tübingen, Germany
Insel PA:
Department of Medicine, University of California San Diego, San Diego, United States
Department of Pharmacology, University of California San Diego, San Diego, United States
Corr M:
Department of Medicine, University of California San Diego, San Diego, United States
Mo JH:
Department of Otorhinolaryngology-Head and Neck Surgery, Dankook University College of Medicine, Chungnam, Republic of Korea
Tao A:
The Second Affiliated Hospital of Guangzhou Medical University (GMU), The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou, China
Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
Yasuda K:
Boston University School of Medicine, Boston, United States
Rifkin IR:
Boston University School of Medicine, Boston, United States
VA Boston Healthcare System, Boston, United States
Broide DH:
Department of Medicine, University of California San Diego, San Diego, United States
Sciammas R:
Center for Comparative Medicine, University of California, Davis, Davis, United States
Webster NJ:
Department of Medicine, University of California San Diego, San Diego, United States
VA San Diego Healthcare System, San Diego, United States
Raz E:
Department of Medicine, University of California San Diego, San Diego, United States
Center for Immunology, Inflammation and Immune-mediated disease, GMU, Guangzhou, China
Green Submitted, Green Published, gold
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