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

Abstract

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. Our goal was to investigate the effects of cannabinoids on ILC2s and their role in asthma. A combination of cannabinoid receptor (CB)₂ knockout (KO) mice, CB₂ 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 CB₂ signaling in human ILC2s. We 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 naive and activated murine pulmonary ILC2s express CB₂. CB₂ signaling did not affect ILC2 homeostasis at steady state, but strikingly it 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 cyclic adenosine monophosphate-response element binding protein (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. Collectively, our results define CB₂ signaling in ILC2s as an important modulator of airway inflammation.