Cargando…

Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses

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 t...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Jihyung, Zhang, Junyan, Chung, Young-Jun, Kim, Jun Hwan, Kook, Chae Min, González-Navajas, José M, Herdman, David S, Nürnberg, Bernd, Insel, Paul A, Corr, Maripat, Mo, Ji-Hun, Tao, Ailin, Yasuda, Kei, Rifkin, Ian R, Broide, David H, Sciammas, Roger, Webster, Nicholas JG, Raz, Eyal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000221/
https://www.ncbi.nlm.nih.gov/pubmed/32014112
http://dx.doi.org/10.7554/eLife.49416
_version_ 1783494000537239552
author Lee, Jihyung
Zhang, Junyan
Chung, Young-Jun
Kim, Jun Hwan
Kook, Chae Min
González-Navajas, José M
Herdman, David S
Nürnberg, Bernd
Insel, Paul A
Corr, Maripat
Mo, Ji-Hun
Tao, Ailin
Yasuda, Kei
Rifkin, Ian R
Broide, David H
Sciammas, Roger
Webster, Nicholas JG
Raz, Eyal
author_facet Lee, Jihyung
Zhang, Junyan
Chung, Young-Jun
Kim, Jun Hwan
Kook, Chae Min
González-Navajas, José M
Herdman, David S
Nürnberg, Bernd
Insel, Paul A
Corr, Maripat
Mo, Ji-Hun
Tao, Ailin
Yasuda, Kei
Rifkin, Ian R
Broide, David H
Sciammas, Roger
Webster, Nicholas JG
Raz, Eyal
author_sort Lee, Jihyung
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7000221
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-70002212020-02-06 Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses Lee, Jihyung Zhang, Junyan Chung, Young-Jun Kim, Jun Hwan Kook, Chae Min González-Navajas, José M Herdman, David S Nürnberg, Bernd Insel, Paul A Corr, Maripat Mo, Ji-Hun Tao, Ailin Yasuda, Kei Rifkin, Ian R Broide, David H Sciammas, Roger Webster, Nicholas JG Raz, Eyal eLife Immunology and Inflammation 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. eLife Sciences Publications, Ltd 2020-02-04 /pmc/articles/PMC7000221/ /pubmed/32014112 http://dx.doi.org/10.7554/eLife.49416 Text en © 2020, Lee et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Lee, Jihyung
Zhang, Junyan
Chung, Young-Jun
Kim, Jun Hwan
Kook, Chae Min
González-Navajas, José M
Herdman, David S
Nürnberg, Bernd
Insel, Paul A
Corr, Maripat
Mo, Ji-Hun
Tao, Ailin
Yasuda, Kei
Rifkin, Ian R
Broide, David H
Sciammas, Roger
Webster, Nicholas JG
Raz, Eyal
Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
title Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
title_full Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
title_fullStr Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
title_full_unstemmed Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
title_short Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
title_sort inhibition of irf4 in dendritic cells by prr-independent and -dependent signals inhibit th2 and promote th17 responses
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000221/
https://www.ncbi.nlm.nih.gov/pubmed/32014112
http://dx.doi.org/10.7554/eLife.49416
work_keys_str_mv AT leejihyung inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT zhangjunyan inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT chungyoungjun inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT kimjunhwan inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT kookchaemin inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT gonzaleznavajasjosem inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT herdmandavids inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT nurnbergbernd inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT inselpaula inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT corrmaripat inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT mojihun inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT taoailin inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT yasudakei inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT rifkinianr inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT broidedavidh inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT sciammasroger inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT websternicholasjg inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses
AT razeyal inhibitionofirf4indendriticcellsbyprrindependentanddependentsignalsinhibitth2andpromoteth17responses