Image_2_The NF-κB Transcription Factor c-Rel Modulates Group 2 Innate Lymphoid Cell Effector Functions and Drives Allergic Airway Inflammation.pdf
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.
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References
- https://doi.org//10.1038/nature08636
- https://doi.org//10.1038/nature08900
- https://doi.org//10.1073/pnas.1003988107
- https://doi.org//10.1016/j.immuni.2011.12.020
- https://doi.org//10.1016/j.jaci.2011.09.041
- https://doi.org//10.3389/fimmu.2018.00840
- https://doi.org//10.1016/j.jaci.2013.05.012
- https://doi.org//10.1016/j.immuni.2015.06.006
- https://doi.org//10.1016/j.cell.2008.01.020
- https://doi.org//10.1002/bies.10306
- https://doi.org//10.1016/j.immuni.2017.08.010
- https://doi.org//10.1016/j.immuni.2019.06.009
- https://doi.org//10.1016/j.jaci.2018.01.028
- https://doi.org//10.1038/ncomms13202
- https://doi.org//10.1038/s41423-018-0182-0
- https://doi.org//10.1038/s41423-020-0404-0
- https://doi.org//10.3109/02770900903089998
- https://doi.org//10.1016/j.cell.2017.08.004
- https://doi.org//10.1124/jpet.103.053819
- https://doi.org//10.1101/gad.9.16.1965
- https://doi.org//10.1038/ni.3308
- https://doi.org//10.1186/1756-0500-3-294
- https://doi.org//10.1016/j.celrep.2018.06.005
- https://doi.org//10.1111/imr.12706
- https://doi.org//10.1002/eji.201545635
- https://doi.org//10.1016/j.immuni.2015.02.007
- https://doi.org//10.1038/mi.2013.114
- https://doi.org//10.1038/mi.2013.92
- https://doi.org//10.1038/s41467-019-08449-x
- https://doi.org//10.1016/j.immuni.2018.05.003
- https://doi.org//10.1093/intimm/11.3.361
- https://doi.org//10.1002/%28SICI%291521-4141%28199812%2928%3A12%3C4299%3A%3AAID-IMMU4299%3E3.0.CO;2-Y
- https://doi.org//10.1093/emboj/19.23.6351
- https://doi.org//10.1038/sj.onc.1207410
- https://doi.org//10.1016/j.cell.2016.12.012
- https://doi.org//10.1084/jem.182.4.1169
- https://doi.org//10.1111/j.1398-9995.2009.02095.x
- https://doi.org//10.1084/jem.20182111
- https://doi.org//10.1084/jem.20130071
- https://doi.org//10.1007/s00281-016-0601-1
- https://doi.org//10.1007/s00281-016-0606-9
- https://doi.org//10.1084/jem.20112691
- https://doi.org//10.1038/mi.2016.90
- https://doi.org//10.4049/jimmunol.170.7.3724
- https://doi.org//10.1128/MCB.12.9.4067
- https://doi.org//10.1016/j.jaci.2015.03.043
- https://doi.org//10.1016/j.immuni.2014.06.016
- https://doi.org//10.4049/jimmunol.1300974
- https://doi.org//10.4049/jimmunol.178.11.7097
- https://doi.org//10.1038/nri3405
- https://doi.org//10.3389/fimmu.2018.02694
- https://doi.org//10.1242/dev.120.10.2991
- https://doi.org//10.4049/jimmunol.1400481
- https://doi.org//10.1073/pnas.082647499
- https://doi.org//10.1038/376167a0
- https://doi.org//10.1111/j.1600-065X.2012.01099.x
- https://doi.org//10.1038/s41586-020-2015-4
- https://doi.org//10.1007/s00109-016-1397-0
- https://doi.org//10.1038/ni.2131
- https://doi.org//10.1038/ni.2045
- https://doi.org//10.1073/pnas.1509070112
- https://doi.org//10.1002/eji.201141947
- https://doi.org//10.1371/journal.pone.0045225
- https://doi.org//10.1016/j.celrep.2018.06.005
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Categories
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity