Cargando…
Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants
IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functio...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310529/ https://www.ncbi.nlm.nih.gov/pubmed/35801586 http://dx.doi.org/10.1172/jci.insight.149825 |
_version_ | 1784753404245966848 |
---|---|
author | Hoyler, Thomas Bannert, Bettina André, Cédric Beck, Damian Boulay, Thomas Buffet, David Caesar, Nadja Calzascia, Thomas Dawson, Janet Kyburz, Diego Hennze, Robert Huppertz, Christine Littlewood-Evans, Amanda Loetscher, Pius Mertz, Kirsten D. Niwa, Satoru Robert, Gautier Rush, James S. Ruzzante, Giulia Sarret, Sophie Stein, Thomas Touil, Ismahane Wieczorek, Grazyna Zipfel, Geraldine Hawtin, Stuart Junt, Tobias |
author_facet | Hoyler, Thomas Bannert, Bettina André, Cédric Beck, Damian Boulay, Thomas Buffet, David Caesar, Nadja Calzascia, Thomas Dawson, Janet Kyburz, Diego Hennze, Robert Huppertz, Christine Littlewood-Evans, Amanda Loetscher, Pius Mertz, Kirsten D. Niwa, Satoru Robert, Gautier Rush, James S. Ruzzante, Giulia Sarret, Sophie Stein, Thomas Touil, Ismahane Wieczorek, Grazyna Zipfel, Geraldine Hawtin, Stuart Junt, Tobias |
author_sort | Hoyler, Thomas |
collection | PubMed |
description | IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type–specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1β or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1β–dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis. |
format | Online Article Text |
id | pubmed-9310529 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-93105292022-07-27 Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants Hoyler, Thomas Bannert, Bettina André, Cédric Beck, Damian Boulay, Thomas Buffet, David Caesar, Nadja Calzascia, Thomas Dawson, Janet Kyburz, Diego Hennze, Robert Huppertz, Christine Littlewood-Evans, Amanda Loetscher, Pius Mertz, Kirsten D. Niwa, Satoru Robert, Gautier Rush, James S. Ruzzante, Giulia Sarret, Sophie Stein, Thomas Touil, Ismahane Wieczorek, Grazyna Zipfel, Geraldine Hawtin, Stuart Junt, Tobias JCI Insight Research Article IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type–specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1β or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1β–dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis. American Society for Clinical Investigation 2022-07-08 /pmc/articles/PMC9310529/ /pubmed/35801586 http://dx.doi.org/10.1172/jci.insight.149825 Text en © 2022 Hoyler et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Hoyler, Thomas Bannert, Bettina André, Cédric Beck, Damian Boulay, Thomas Buffet, David Caesar, Nadja Calzascia, Thomas Dawson, Janet Kyburz, Diego Hennze, Robert Huppertz, Christine Littlewood-Evans, Amanda Loetscher, Pius Mertz, Kirsten D. Niwa, Satoru Robert, Gautier Rush, James S. Ruzzante, Giulia Sarret, Sophie Stein, Thomas Touil, Ismahane Wieczorek, Grazyna Zipfel, Geraldine Hawtin, Stuart Junt, Tobias Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants |
title | Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants |
title_full | Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants |
title_fullStr | Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants |
title_full_unstemmed | Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants |
title_short | Nonhematopoietic IRAK1 drives arthritis via neutrophil chemoattractants |
title_sort | nonhematopoietic irak1 drives arthritis via neutrophil chemoattractants |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310529/ https://www.ncbi.nlm.nih.gov/pubmed/35801586 http://dx.doi.org/10.1172/jci.insight.149825 |
work_keys_str_mv | AT hoylerthomas nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT bannertbettina nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT andrecedric nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT beckdamian nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT boulaythomas nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT buffetdavid nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT caesarnadja nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT calzasciathomas nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT dawsonjanet nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT kyburzdiego nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT hennzerobert nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT huppertzchristine nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT littlewoodevansamanda nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT loetscherpius nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT mertzkirstend nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT niwasatoru nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT robertgautier nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT rushjamess nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT ruzzantegiulia nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT sarretsophie nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT steinthomas nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT touilismahane nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT wieczorekgrazyna nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT zipfelgeraldine nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT hawtinstuart nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants AT junttobias nonhematopoieticirak1drivesarthritisvianeutrophilchemoattractants |