Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses.
Jihyung LeeJunyan ZhangYoung-Jun ChungJun Hwan KimChae Min KookJosé M González-NavajasDavid S HerdmanBernd NürnbergPaul A InselMaripat CorrJi-Hun MoAilin TaoKei YasudaIan R RifkinDavid H BroideRoger SciammasNicholas Jg WebsterEyal RazPublished in: eLife (2020)
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.
Keyphrases
- dendritic cells
- cell cycle
- transcription factor
- regulatory t cells
- immune response
- binding protein
- protein kinase
- signaling pathway
- machine learning
- deep learning
- gene expression
- metabolic syndrome
- high fat diet induced
- microbial community
- adipose tissue
- dna methylation
- oxidative stress
- type diabetes
- single cell
- pi k akt
- wild type
- anti inflammatory
- endoplasmic reticulum stress
- genome wide identification