|Nrf2 activation alleviates lung inflammation by inducing ILC2 death|
|Type 2 innate lymphoid cells (ILC2) play an important role in allergy by secreting Th2 cytokines (like IL5 and IL-13) to induce eosinophil recruitment and enhance mucus secretion from goblet cells, respectively. Oxidative stress is induced during allergy, which leads to many genes activated. Nrf2 is a transcription factor that recognizes antioxidant responsive elements, activation of which results in expression of genes including HO-1 and Nqo-1. It has been reported that Nrf2-deficient mice exhibit exacerbated asthma due to excessive Th2 cytokines, whereas activation of Nrf2 alleviates allergy. However, the effects of Nrf2 activation on the fate of ILC2 remained unclear until Dr. Tanaka’s team published their data in the Journal of Immunology (here).
ILC2 were induced in vitro by intraperitoneal injection of IL25 an IL33, and lung ILC2 were collected for further analyses. The investigators found that ILC2 collected from Nrf2-KO mice harbored increased proliferation, and activation of Nrf2 by CDDO-Im elevated the level of cell death. Subsequently, authors sought to explore the mechanisms of Nrf2-mediated cell death in ILC2. They ruled out the effects of apoptosis, necroptosis, necrosis, or ferroptosis in this process. Moreover, activation of Nrf2 by CDDO-Im in allergic lung inflammation animals reduced the number of lung ILC2, and attenuated the disease severity by reducing eosinophil recruitment as well as decreasing mucus production. This protective effect was Nrf2-dependent.
This study highlights the importance of Nrf2 as a negative regulator of ILC2. However, a number of questions have been left unanswered. First, the mechanisms of Nrf2-mediated ILC2 death are still unknown. Although the authors attempted to determine the effects of apoptosis and other types of cell death in this contest, the cellular mechanisms remain unclear. We speculate that if a bias-free approach, like mRNA arrays or mRNA sequencing, would help to find unappreciated genes that are involved in Nrf2-mediated ILC2 death. Second, we do not know yet if Nrf2 is ILC2-specific. It is probable that other cell types in inflammation are controlled by Nrf2. Last, the efficacies of Nrf2 and corticosteroids in treatment of lung allergy need to be compared.
In conclusion, Nrf2 is a negative regulator of ILC2 and manipulation of Nrf2 can be used for allergy treatment. Further investigations are warranted for the mechanisms of Nrf2-mediated cell death.