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The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation.
- Source :
-
Frontiers in immunology [Front Immunol] 2021 Nov 16; Vol. 12, pp. 664218. Date of Electronic Publication: 2021 Nov 16 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- 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 <superscript>-/-</superscript> 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.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2021 Mindt, Krisna, Duerr, Mancini, Richer, Vidal, Gerondakis, Langlais and Fritz.)
- Subjects :
- Animals
Asthma immunology
Asthma pathology
Disease Models, Animal
Female
Gene Expression
In Vitro Techniques
Interleukin-33 immunology
Lung pathology
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B metabolism
Proto-Oncogene Proteins c-rel deficiency
Proto-Oncogene Proteins c-rel genetics
Immunity, Innate
Lung immunology
Lymphocyte Subsets immunology
Proto-Oncogene Proteins c-rel immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 34867937
- Full Text :
- https://doi.org/10.3389/fimmu.2021.664218