Interleukin‐33 increases type 2 innate lymphoid cell count and their activation in eosinophilic asthma

BACKGROUND: Interleukin‐33 (IL‐33) exacerbates asthma probably through type 2 innate lymphoid cells (ILC2s). Nevertheless, the association between eosinophilic asthma (EA) and ILC2s remains obscure, and the mechanisms by which IL‐33 affects ILC2s are yet to be clarified. METHODS: ILC2s were evaluated in peripheral blood mononuclear cells, induced sputum, and bronchoalveolar lavage fluid obtained from patients with EA. Confocal microscopy was performed to locate ILC2s in lung tissue and the mRNA expression of ILC2‐related genes was also evaluated in the EA model. The proliferation of ILC2s isolated from humans and mice was assessed following IL‐33 or anti‐IL‐33 stimulation. RESULTS: The counts, activation, and mRNA expression of relevant genes in ILC2s were higher in PBMCs and airways of patients with EA. In addition, ILC2 cell counts correlated with Asthma control test, blood eosinophil count, Fractional exhaled nitric oxide level, and predicted eosinophilic airway inflammation. IL‐33 induced stronger proliferation of ILC2s and increased their density around blood vessels in the lungs of mice with EA. Moreover, IL‐33 treatment increased the counts and activation of ILC2s and lung inflammatory scores, whereas anti‐IL‐33 antibody significantly reversed these effects in EA mice. Finally, IL‐33 enhanced PI3K and AKT protein expression in ILC2s, whereas inhibition of the PI3K/AKT pathway decreased IL‐5 and IL‐13 production by ILC2s in EA. CONCLUSIONS: ILC2s, especially activated ILC2s, might be critical markers of EA. IL‐33 can induce and activate ILC2s in the lungs via the PI3K/AKT pathway in EA. Thus, using anti‐IL‐33 antibody could be a part of an effective treatment strategy for EA.