IL-33 affects the IL-4-induced development of group 2 innate lymphoid cells in neonatal lungs

Abstract

Abstract Abundant IL-33 is produced by alveolar type 2 cells during lung alveolarization phase in the neonatal stage. It promotes Th2 response and may facilitate ILC2 development with IL-4 stimulation. IL-4 has been found to induce IL-10 +ILC2s in the lung environment, however, it is still unknown whether ILC1/2/3 transdifferentiation and IL-10 +ILC2 functions in neonatal lungs are regulated by IL-33. Therefore, we aimed to investigate the regulation role of IL-33 in lung ILC development during neonatal period. To identify the key cytokines under IL-33 regulation in neonatal lungs, we used antibody staining to characterize ILC1/2/3 and measured the cytokines relevant to ILC2 functions in WT and IL-33 −/−mice. We found that while lung ILC2s increased from postnatal day (PND) 14 to 28 in WT mice, ILC1s and ILC3s decreased in the same period. However, we found that there were significantly decreased ILC2s on PND 21 in the lungs of IL-33 −/−mice when compared with WT mice. We also found that increase in IL-33, IL-4, IL-10 on PND 28 in the lungs of WT mice, which was not apparent in IL-33 −/−mice. The sorted neonatal lung ILC2s may secrete more IL-10 after stimulated with IL-4 and IL-33 when compared with adult lung ILC2s from either WT or IL-33 −/−mice. Moreover, in vitrocultured ILC populations from IL-33 −/−mice after stimulated with IL-4 and IL-33 may enhance ILC1/3 transdifferentiate into IL-10 +ILC2s. Our results showed that IL-33 contributes to ILCs differentiate towards IL-10 +ILC2 through IL-4 and IL-33 stimulation during lung alveolarization phase. As IL-10 +ILC2s have been found to play a regulatory role in allergy, the development of IL-10 +ILC2s during neonatal period may be critical for asthma prevention.