Cannabinoid receptor 2 engagement promotes group 2 innate lymphoid cell expansion and enhances airway hyperreactivity.

Background: Cannabinoids modulate the activation of immune cells and physiologic processes in the lungs. Group 2 innate lymphoid cells (ILC2s) are central players in type 2 asthma, but how cannabinoids modulate ILC2 activation remains to be elucidated.

Objective: Our goal was to investigate the effects of cannabinoids on ILC2s and their role in asthma.

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

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

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