Journal
FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.664218
Keywords
group 2 innate lymphoid cell (ILC2); IL-33; c-Rel; type 2 immunity; airway inflammation
Categories
Funding
- Canadian Institutes of Health Research (CIHR) [FDN-148405, PJT-175173]
- Canadian Foundation of Innovation (CFI) [38958]
- CIHR New Investigator Award
- Canada Foundation for Innovation John R. Evans Leaders Fund award (CFI-JELF) [38033]
- Startup Funds from the McGill University Faculty of Medicine
- CIHR Project Grant [168959]
- FRQS, Chercheur-Boursier Junior 1 Award [284497]
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The NF-kappa B subunit c-Rel is crucial for effective innate pulmonary type 2 immune responses, regulated by IL-33-induced expression and nuclear translocation. Intrinsic deficiency of c-Rel in ILC2s does not affect development or homeostatic numbers, but alters activation status and the expression of key stimulatory receptors and type 2 signature cytokines. Rel(-/-) mice suggest that c-Rel promotes acute ILC2-driven allergic airway inflammation, highlighting its potential as a therapeutic target for allergic asthma.
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)-kappa B family transcription factors. While it is known that activating IL-33 receptor signaling results in downstream NF-kappa B activation, the underlying molecular mechanisms remain elusive. Here, we found that the NF-kappa B 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.
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