The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation

Group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and orchestration of early type 2 immune responses. Upon tissue damage, ILC2s are activated by alarmins such as IL-33 and rapidly secrete large amounts of type 2 signature cytokines. ILC2 activation is governed by a network of t...

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Autores principales:	Barbara C. Mindt, Sai Sakktee Krisna, Claudia U. Duerr, Mathieu Mancini, Lara Richer, Silvia M. Vidal, Steven Gerondakis, David Langlais, Jörg H. Fritz
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	group 2 innate lymphoid cell (ILC2) IL-33 c-Rel type 2 immunity airway inflammation Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/71c35d55ad3341a481a892ff468e1673
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spelling	oai:doaj.org-article:71c35d55ad3341a481a892ff468e16732021-11-16T07:00:29ZThe NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation1664-322410.3389/fimmu.2021.664218https://doaj.org/article/71c35d55ad3341a481a892ff468e16732021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.664218/fullhttps://doaj.org/toc/1664-3224Group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and orchestration of early type 2 immune responses. Upon tissue damage, ILC2s are activated by alarmins such as IL-33 and rapidly secrete large amounts of type 2 signature cytokines. ILC2 activation is governed by a network of transcriptional regulators including nuclear factor (NF)-κB family transcription factors. While it is known that activating IL-33 receptor signaling results in downstream NF-κB activation, the underlying molecular mechanisms remain elusive. Here, we found that the NF-κB subunit c-Rel is required to mount effective innate pulmonary type 2 immune responses. IL-33-mediated activation of ILC2s in vitro as well as in vivo was found to induce c-Rel mRNA and protein expression. In addition, we demonstrate that IL-33-mediated activation of ILC2s leads to nuclear translocation of c-Rel in pulmonary ILC2s. Although c-Rel was found to be a critical mediator of innate pulmonary type 2 immune responses, ILC2-intrinsic deficiency of c-Rel did not have an impact on the developmental capacity of ILC2s nor affected homeostatic numbers of lung-resident ILC2s at steady state. Moreover, we demonstrate that ILC2-intrinsic deficiency of c-Rel alters the capacity of ILC2s to upregulate the expression of ICOSL and OX40L, key stimulatory receptors, and the expression of type 2 signature cytokines IL-5, IL-9, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Collectively, our data using Rel−/− mice suggest that c-Rel promotes acute ILC2-driven allergic airway inflammation and suggest that c-Rel may contribute to the pathophysiology of ILC2-mediated allergic airway disease. It thereby represents a promising target for the treatment of allergic asthma, and evaluating the effect of established c-Rel inhibitors in this context would be of great clinical interest.Barbara C. MindtBarbara C. MindtSai Sakktee KrisnaSai Sakktee KrisnaClaudia U. DuerrMathieu ManciniMathieu ManciniLara RicherSilvia M. VidalSilvia M. VidalSteven GerondakisDavid LanglaisDavid LanglaisDavid LanglaisJörg H. FritzJörg H. FritzJörg H. FritzJörg H. FritzFrontiers Media S.A.articlegroup 2 innate lymphoid cell (ILC2)IL-33c-Reltype 2 immunityairway inflammationImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	group 2 innate lymphoid cell (ILC2) IL-33 c-Rel type 2 immunity airway inflammation Immunologic diseases. Allergy RC581-607
spellingShingle	group 2 innate lymphoid cell (ILC2) IL-33 c-Rel type 2 immunity airway inflammation Immunologic diseases. Allergy RC581-607 Barbara C. Mindt Barbara C. Mindt Sai Sakktee Krisna Sai Sakktee Krisna Claudia U. Duerr Mathieu Mancini Mathieu Mancini Lara Richer Silvia M. Vidal Silvia M. Vidal Steven Gerondakis David Langlais David Langlais David Langlais Jörg H. Fritz Jörg H. Fritz Jörg H. Fritz Jörg H. Fritz The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation
description	Group 2 innate lymphoid cells (ILC2s) play a key role in the initiation and orchestration of early type 2 immune responses. Upon tissue damage, ILC2s are activated by alarmins such as IL-33 and rapidly secrete large amounts of type 2 signature cytokines. ILC2 activation is governed by a network of transcriptional regulators including nuclear factor (NF)-κB family transcription factors. While it is known that activating IL-33 receptor signaling results in downstream NF-κB activation, the underlying molecular mechanisms remain elusive. Here, we found that the NF-κB subunit c-Rel is required to mount effective innate pulmonary type 2 immune responses. IL-33-mediated activation of ILC2s in vitro as well as in vivo was found to induce c-Rel mRNA and protein expression. In addition, we demonstrate that IL-33-mediated activation of ILC2s leads to nuclear translocation of c-Rel in pulmonary ILC2s. Although c-Rel was found to be a critical mediator of innate pulmonary type 2 immune responses, ILC2-intrinsic deficiency of c-Rel did not have an impact on the developmental capacity of ILC2s nor affected homeostatic numbers of lung-resident ILC2s at steady state. Moreover, we demonstrate that ILC2-intrinsic deficiency of c-Rel alters the capacity of ILC2s to upregulate the expression of ICOSL and OX40L, key stimulatory receptors, and the expression of type 2 signature cytokines IL-5, IL-9, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Collectively, our data using Rel−/− mice suggest that c-Rel promotes acute ILC2-driven allergic airway inflammation and suggest that c-Rel may contribute to the pathophysiology of ILC2-mediated allergic airway disease. It thereby represents a promising target for the treatment of allergic asthma, and evaluating the effect of established c-Rel inhibitors in this context would be of great clinical interest.
format	article
author	Barbara C. Mindt Barbara C. Mindt Sai Sakktee Krisna Sai Sakktee Krisna Claudia U. Duerr Mathieu Mancini Mathieu Mancini Lara Richer Silvia M. Vidal Silvia M. Vidal Steven Gerondakis David Langlais David Langlais David Langlais Jörg H. Fritz Jörg H. Fritz Jörg H. Fritz Jörg H. Fritz
author_facet	Barbara C. Mindt Barbara C. Mindt Sai Sakktee Krisna Sai Sakktee Krisna Claudia U. Duerr Mathieu Mancini Mathieu Mancini Lara Richer Silvia M. Vidal Silvia M. Vidal Steven Gerondakis David Langlais David Langlais David Langlais Jörg H. Fritz Jörg H. Fritz Jörg H. Fritz Jörg H. Fritz
author_sort	Barbara C. Mindt
title	The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation
title_short	The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation
title_full	The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation
title_fullStr	The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation
title_full_unstemmed	The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation
title_sort	nf-κb transcription factor c-rel modulates group 2 innate lymphoid cell effector functions and drives allergic airway inflammation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/71c35d55ad3341a481a892ff468e1673
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The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation

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