Pulmonary NK cells prevent allergic airway sensitization: Regulation by CB2 cannabinoid receptors

Abstract

Abstract Allergic asthma is a chronic inflammatory disease involving the interaction between the innate and adaptive immune response. Endogenously generated cannabinoids, acting via CB receptors play important roles in both homeostatic and inflammatory processes. CB2-active compounds are known to impact innate immunity including responses by monocytes and NK cells. However, the contribution of pulmonary NK cells and CB2-active endocannabinoids to the innate events preceding sensitization of the airways to the common house dust mite (HDM) allergen is unclear. We investigated the significance of CB2 activation during allergen-triggered pulmonary inflammation and NK cell effector function. Allergic airway inflammation was induced in mice by sensitization via the airways by intranasal HDM instillation, and responses in wild type (WT) and CB2-deficient (CB2−/−) mice were compared. Mice lacking CB2 receptor exhibited elevated numbers of pulmonary NK cells yet were resistant to the induction of allergic inflammation and showed diminished airway hyperreactivity, pulmonary eosinophilia, TH2 cytokine production and mucus secretion after allergen inhalation. Cellular depletion and adoptive transfer studies were undertaken to dissect the mechanisms involved. Depletion of NK cells restored HDM responsiveness. Conversely, transfer of CB2−/− NK cells into WT mice suppressed the allergic airway inflammation and was associated with a reduction in monocyte-derived dendritic cells but elevated CX3CL1 release and recruitment of Ly6C−CX3CR1+ monocytes. These studies established a crucial role for CB2 activation in allergic lung disease via regulation of NK cell function and identified novel therapeutic targets for treatment of asthma.