Abstract Background Corticosteroids are crucial to anti-inflammatory therapy for asthma. However, some asthma patients exhibit steroid insensitivity. Group 2 innate lymphoid cells (ILC2s) are increased in the airways of severe asthma and are implicated in steroid insensitivity and refractory asthma. This study aimed to elucidate mechanisms underlying steroid insensitivity of ILC2s by focusing on tumor necrosis factor-like ligand 1A (TL1A)/death receptor 3 (DR3) signaling, a member of the TNF superfamily. Methods ILC2s were isolated from nasal polyp tissues of patients with asthma and chronic rhinosinusitis. The isolated ILC2s cultured with IL-2, IL-7, and IL-33 were stimulated with TL1A to evaluate type-2 cytokine production. The effects of dexamethasone on IL-5 production and on apoptosis were also assessed. Intracellular signaling pathways were evaluated using flow cytometry and Western blotting. Results IL-5 was produced from ILC2s after culturing with IL-2, IL-7, and IL-33, and decreased by dexamethasone. When ILC2s were cultured and treated with TL1A, IL-5 production was not suppressed by dexamethasone. Furthermore, TL1A reduced the rate of steroid-induced apoptosis in ILC2s. The expression of NF-κB p52, a transcription factor of non-canonical NF-κB pathway, was also upregulated following TL1A stimulation. NF-κB p52 expression remained high even after dexamethasone treatment when cells were stimulated with TL1A, compared to those without TL1A. Conclusions These findings suggest that TL1A/DR3 signaling plays a crucial role in steroid insensitivity of ILC2s by activating NF-κB p52 and inhibiting apoptosis. This abstract is funded by: none
Matsuyama et al. (Fri,) studied this question.