Allergic diseases, including allergic asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis and food allergy affect ~20% of the global population and are continually increasing. Atopic dermatitis (AD) and severe asthma have been labelled as unmet clinical needs since the majority of patients require periodical symptomatic therapy with topical corticosteroids and/or calcineurin inhibitors, both of which are associated with long-term side effects. Our goal is to search for novel, effective ways to treat allergic inflammatory diseases by specifically analyzing activating and inhibitory receptors on the mast cells (MCs) and the eosinophils (Eos ), the key effector cells of allergy. Importantly CB1 and CB2 receptors are both expressed on MCs and CB2 is found on Eos. Endocannabinoids (EC) have recently been ascribed with potential anti-inflammatory properties but their activity on MCs, Eos and in allergy is unclear as yet as evident from what discussed below. Hence our interest to define better EC on our target cells in allergy.
It has been shown that CB1 and CB2 on MCs have anti-inflammatory effects. CB1 downregulates MC degranulation, while CB2 downregulates the release of pro-inflammatory mediators. Blocking of CB1 on MCs in the human hair follicles stimulates degranulation and increases cell numbers without affecting MC proliferation in situ. Moreover CB1 activation of bronchial nerve endings has bronchodilatory effects and therefore might be beneficial in asthma. On the other hand, 2-arachidonoylglycerol and the selective agonist JWH-133 induce Eos chemotaxis, shape change, adhesion production of reactive oxygen species and increase in CD11b expression, via CB2 activation . Similarly, systemic application of JWH-133 worsened asthma by enhancing Eos numbers suggesting the importance of an antagonistic approach directed to the CB2 receptor. Indeed thespecific CB2 antagonist SR144528 attenuates both the recruitment of Eos and ear swelling in a murine chronic contact dermatitis model while CB2 agonists have been shown to have antipruritic activity. Nevertheless, the CB2 agonist Gp1a has been shown to downregulate IgE levels in antigen-immunized mice. In patients with asthma, allergen challenge was found to increase anandamide levels in the BAL and to increase airway epithelium permeability) indicating a potential role in enhancing asthma severity. In contrast, the CB1/CB2 agonist CP55,940 can effectively prevent antigen-induced asthma-like reactions in guinea pigs. Altogether, these studies indicate that CB1, CB2 and EC are potential but complex therapeutic targets for the treatment of allergic inflammation. On MCs, CB1/CB2 activation is mostly anti-inflammatory while on Eos CB2 activation is pro-inflammatory. Therefore, a differential approach using CB1/CB2 agonists and antagonists in the treatment of allergic conditions will be required,
To perform a comprehensive in vitro/ in vivo study to dissect the potential of stimulation or blockade of CB1 and/or CB2 receptors as expressed by mast cells and eosinophils in treating allergic inflammatory diseases.
Specific aims/Plan of work
We propose to study receptor expression and effect of their selective activation or blockade (by synthetic compounds) on effector functions of human and murine derived MCs and Eos. CB1 and CB2 KO mice or these mice conditionally KO for MCs and /or Eos receptors will be utilized to further assess the EC system. In vivo in a murine model of AD and of asthma we will assess the potential anti-allergic properties of compounds selected from in vitro studies. Moreover we will also evaluate the potential pro-resolving capacity of the EC system in these 2 models of allergic diseases by itself and by its interaction with specialized pro-resolving lipid mediators.
*The Hebrew University of Jerusalem, Jerusalem, Israel