Abstract
Group 2 innate lymphoid cells (ILC2) increase in frequency in eczema and allergic asthma patients, and thus represent a new therapeutic target cell for type-2 immune-mediated disease. The bromodomain and extra-terminal (BET) protein family of epigenetic regulators are known to support the expression of cell cycle and pro-inflammatory genes during type-1 inflammation, but have not been evaluated in type-2 immune responses. We isolated human ILC2 and examined the capacity of the BET protein inhibitor, iBET151, to modulate human ILC2 activation following IL-33 stimulation. iBET151 profoundly blocked expression of genes critical for type-2 immunity, including type-2 cytokines, cell surface receptors and transcriptional regulators of ILC2 differentiation and activation. Furthermore, in vivo administration of iBET151 during experimental mouse models of allergic lung inflammation potently inhibited lung inflammation and airways resistance in response to cytokine or allergen exposure. Thus, iBET151 effectively prevents human ILC2 activation and dampens type-2 immune responses.
Highlights
Innate lymphoid cells (ILCs) have emerged as strategic players in inflammation and immunity, and represent new therapeutic targets in disease [1, 2]
Treatment of ILC2s with iBET151 potently inhibited the transcription of the genes encoding IL-4, IL-5, and IL-13, as well as GM-CSF and CSF1 (Figures 1B,D)
The screen identified the inhibition of RBPJ, a critical transcription factor in Notch signaling and ILC2 differentiation; BATF, a component of the BATF–AP1–IRF4 complex that regulates the type-2 cytokine locus in Th2 cells; and microRNA-155 host gene (HG) that is processed to give miR155, which has been reported to support mouse ILC2 function (Figures 1B,D)
Summary
Innate lymphoid cells (ILCs) have emerged as strategic players in inflammation and immunity, and represent new therapeutic targets in disease [1, 2]. ILC2s were first described as playing important roles in the initiation of inflammation at mucosal barrier surfaces in response to infection or tissue damage [1, 4]. It is apparent that ILC2s can play more complex roles throughout the duration of immune responses, participating in the transition from innate to adaptive immunity and contributing to chronic inflammation. The proximity of ILC2s to epithelial surfaces and their constitutive strategic positioning in other tissues throughout the body ensures that, in spite of their rarity, ILC2s are able to regulate immune homeostasis and respond rapidly to damage or infection.
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