Cannabinoid Receptor II engagement promotes ILC2 expansion and enhances ILC2-dependent airway hyperreactivity

Background: Cannabinoids modulate the activation of immune cells and physiological processes in the lungs. Group-2 innate lymphoid cells (ILC2)s are central players in type-2 asthma, but how cannabinoids modulate ILC2 activation remains to be elucidated OBJECTIVE: Our goal is to investigate the effects of cannabinoids on ILC2s and their role in asthma.

Methods: A combination of Cannabinoid receptor (CB)2 KO mice, CB2 antagonist and agonist were used in the mouse models of IL-33, IL-25 and Alternaria alternata ILC2-dependent airway inflammation, and RNA sequencing was performed to assess transcriptomic changes in ILC2s. Humanized mice were used to assess the role of CB2 signaling in human ILC2s.

Results: We here provide evidence that CB2 signaling in ILC2s is important for the development of ILC2-driven airway inflammation in both mice and human. We showed that both naïve and activated murine pulmonary ILC2s express CB2. CB2 signaling did not affect ILC2 homeostasis at steady state, but strikingly stimulated ILC2 proliferation and function upon activation. As a result, ILC2s lacking CB2 induced lower lung inflammation, as we made similar observations using a CB2 antagonist. Conversely, CB2 agonism remarkably exacerbated ILC2-driven airway hyperreactivity and lung inflammation. Mechanistically, transcriptomic and protein analysis revealed that CB2 signaling induced CREB phosphorylation in ILC2s. Human ILC2s expressed CB2, as CB2 antagonism and agonism showed opposing effects on ILC2 effector function and development of airway hyperreactivity in humanized mice.

Conclusion: Collectively, our results define CB2 signaling in ILC2s as an important modulator of airway inflammation.