Could we co-opt the cannabinoid system for asthma therapy?

Asthma is a major health problem of increasing prevalence affecting both children and adults with a high socio-economic impact [1]. Around 350 million people suffer from asthma, leading to a significant impairment of the patients’ quality of life and to an annual care costs of around €20 billion in Europe [1–3]. Asthma is a chronic inflammatory disorder of the airways characterized by variable and recurring symptoms (wheezing, reversible airflow obstruction, chest tightness and cough), bronchial hyperresponsiveness (BHR) and chronic airway inflammation [4,5]. Asthma is a highly heterogeneous syndrome encompassing different phenotypes/endotypes. According to the expression levels of type 2 biomarkers and clinical features, asthma can be categorized as follows: i) type 2 immune-mediated asthma, which is characterized by blood eosinophilia (>150 cells/μL), tissue eosinophilia (>2% in sputum), elevated serum IgE levels and clinically allergen-driven, elevated FeNO (>19.5 ppb) and upper airways comorbidities; ii) non-type 2 asthma encompassing neutrophilic, paucigranulocytic and obesity-associated asthma [4,6,7]. Alarmins TSLP, IL-33 and IL25 produced by bronchial epithelial cells (BECs) activate dendritic cells (DCs) and type 2 innate lymphoid cells (ILC2s), thus initiating and perpetuating type 2 inflammatory responses, characterized by increased numbers of CD4 Th2 cells and ILC2s in lungs and peripheral blood [5]. Type 2 cytokines (IL-4, IL-13, IL-5 and IL-9) contribute to eosinophilia, BHR, mucus production and IgE levels [5,8,9]. Non-type 2 asthma is characterized by increased levels of Th1 and/or Th17 cells, which together with macrophages, ILC subsets, fibroblasts, smooth muscle cells and BECs’ oxidative stress promote apoptosis of bronchial epithelium and neutrophil recruitment, leading to severe clinical manifestations [6,10]. Allergic sensitization and infections are risk factors for asthma development and progression to difficult-to-treat and severe asthma [11,12]. Severe asthma represent 5–10% of the entire asthma population but it is associated with significant comorbidity (including oral corticosteroid side (OCS) effects) and with the highest healthcare resource use [1,4,13]. Corticosteroids and bronchodilators represent the mainstay treatment for asthma and many patients remain controlled with them. However, the management of severe asthma continues to be challenging. The recent advent of biologicals was a major breakthrough in the treatment of severe type 2 asthma [1]. Biologicals show efficacy in reducing exacerbations, improving lung function, and reducing OCS, but the main drawbacks include the high costs of the treatment and the lack of suitable predictive biomarkers for patient selection. Importantly, they show poor efficacy for severe non-type 2 asthmatic patients. Therefore, there is an unmet need for the development of novel therapies for the prevention and treatment of severe asthma. The human endogenous cannabinoid system (ECS) is a complex signaling network involved in a large number of physiological processes [14,15]. The ECS comprises the endocannabinoid ligands (anandamide (AEA), 2-arachidonoylglycerol (2-AG) as well as other minor ω-6 (n-6) and ω-3 (n-3) fatty acids compounds), the proteins related to their synthesis (N-acyl-phosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D (NAPE-PLD) and sn-1-specific diacylglycerol lipase (DAGL)) and degradation (fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)) and the cannabinoid receptors (CBRs). Endocannabinoids bind to the canonical G-protein coupled cannabinoid receptor 1 (CB1) and 2 (CB2). CB1 is largely expressed in the central nervous system but also in peripheral tissues and immune cells [16]. CB2 is mainly expressed in immune cells, but also in neurons and other cell types [17]. Alternative CBRs include other orphan GPCRs, TRPVs or PPARs [14,15]. Phytocannabinoids from Cannabis sativa L. , marijuana, such as Δ-tetrahydrocannabinol (ΔTHC), also activate CBRs and downstream signaling pathways regulating proliferation, differentiation, cell survival, metabolism or immunity [15]. Similarly, a plethora of functional synthetic cannabinoids have been generated, including agonists with similar affinity for CB1/CB2 (WIN55212–2 or HU210), CB1selective (R-(+)-methanandamide), CB2-selective (HU308) and selective antagonists for CB1 (rimonabant) or CB2 (AM630), among others [14,15]. Alterations in the ECS signaling pathways and changes in the endocannabinoid levels are associated to different diseases such as, neurological and neuropsychiatric conditions, pain and inflammation, obesity, metabolic disorders, septic shock and other inflammatory immune-mediated diseases, including asthma [14,15]. Most animal studies showed cannabinoids as potent suppressors of immune-mediated responses in asthma, but some contradictory results have been reported [15]. Δ-THC prevents the IgE sensitization and pro-inflammatory cytokines in the lung [18]. Similarly, cannabidiol (CBD), a major active ingredient of marijuana that does not produce psychotropic