1. Body of the article

Asthma is a major health problem of increasing prevalence affecting both children and adults with a high socio-economic impact [Citation1]. 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 [Citation1–3]. 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 [Citation4,Citation5]. 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⁻¹), 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 [Citation4,Citation6,Citation7]. Alarmins TSLP, IL-33 and IL-25 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 [Citation5]. Type 2 cytokines (IL-4, IL-13, IL-5 and IL-9) contribute to eosinophilia, BHR, mucus production and IgE levels [Citation5,Citation8,Citation9]. 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 [Citation6,Citation10]. Allergic sensitization and infections are risk factors for asthma development and progression to difficult-to-treat and severe asthma [Citation11,Citation12]. 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 [Citation1,Citation4,Citation13]. 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 [Citation1]. 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 [Citation14,Citation15]. 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 [Citation16]. CB2 is mainly expressed in immune cells, but also in neurons and other cell types [Citation17]. Alternative CBRs include other orphan GPCRs, TRPVs or PPARs [Citation14,Citation15]. Phytocannabinoids from Cannabis sativa L., marijuana, such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC), also activate CBRs and downstream signaling pathways regulating proliferation, differentiation, cell survival, metabolism or immunity [Citation15]. Similarly, a plethora of functional synthetic cannabinoids have been generated, including agonists with similar affinity for CB1/CB2 (WIN55212–2 or HU210), CB1-selective (R-(+)-methanandamide), CB2-selective (HU308) and selective antagonists for CB1 (rimonabant) or CB2 (AM630), among others [Citation14,Citation15]. 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 [Citation14,Citation15].

Most animal studies showed cannabinoids as potent suppressors of immune-mediated responses in asthma, but some contradictory results have been reported [Citation15]. Δ⁹-THC prevents the IgE sensitization and pro-inflammatory cytokines in the lung [Citation18]. Similarly, cannabidiol (CBD), a major active ingredient of marijuana that does not produce psychotropic effects, restores lung function and impairs asthma features in a mouse model of allergic asthma by reducing cytokine production, airway remodeling and BHR [Citation19]. Supporting these data, FAAH and MAGL inhibitor treatments impairs airway inflammation and BHR in an OVA-induced allergic inflammation guinea pig model [Citation20]. Different studies convincingly demonstrated that endocannabinoids, synthetic cannabinoids and phytocannabinoids can also reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release [Citation21]. Some of the beneficial effects of cannabinoids in these asthma models might be partially due to their reported bronchodilatory properties. For example, inhaled AEA reduces leukotriene D4-induced airway obstruction in guinea pigs [Citation22] and similar effects have been also reported for CBD [Citation23]. In contrast, other mice studies showed that CB2 enhances eosinophil recruitment and responsiveness in the lung, thus worsening allergen-induced pulmonary inflammation [Citation24]. In the same line, CB2 knockout mice display reduced airway inflammation than wild-type mice upon house dust mite sensitization and provocation, which dependent on the negative regulation exerted by NK cells on ILC2s in a CB2-dependent manner [Citation25]. More recently, it was shown that CB2 directly regulates ILC2s by promoting their expansion and functional activation as key contributors of airway inflammation both in mice and humans [Citation26]. However, other studies in guinea pig models demonstrated potential beneficial effects of CB2 activation in the inhibition of antigen-induced plasma extravasation in the airways, inhibition of neurogenic inflammation as well as in the prevention of asthma development [Citation27–29]. Collectively, these data indicate that cannabinoids suppress asthma features in the airways, but there might be conditions under which cannabinoids might also exert pro-inflammatory and deleterious properties.

The first evidence of the potential therapeutic role of cannabinoids in asthma was reported in the 1970s when initial studies demonstrated bronchodilatory properties of marijuana smoke and oral administration of Δ⁹-THC [Citation30]. However, in some asthmatic patients aerosolized Δ⁹-THC induced bronchospasm [Citation31], which together with concerns related to its psychotropic effects have hampered further clinical developments. Mechanistically, CB1 activation control nerve-mediated cholinergic contractions and prevented BHR both in mice and humans, confirming a probable protective role in asthma [Citation32–34]. AEA can exert dual effects on bronchial responsiveness in rodents. AEA inhibits capsaicin-induced BHR in axon terminals of airways nerves in a CB1 dependent manner but induces bronchospasm when the constricting tone exerted by the vagus nerve is removed [Citation35], which might explain some of the paradoxical bronchoconstrictory responses reported in asthmatic patients. Discrepancies noted between mice and human data might be also related to the capacity of allergenic proteins contained in cannabis to induce allergic responses in sensitized marijuana smokers [Citation36]. At this regard, it is important to clearly differentiate between the role of allergenic proteins contained in cannabis able to trigger allergic reactions and cannabinoids lipid mediators as small molecules with anti-inflammatory and immunomodulatory features. The use of proper synthetic cannabinoids as potential therapeutic drugs for asthma might completely overcome potential risk associated to cannabis allergic sensitization. Although data in humans are still scarce compare to animal models [Citation15], CB1 plays a potent inhibitory role on human mast cell activation in the airway mucosa [Citation37]. Increased levels of AEA in the bronchoalveolar lavage fluid of asthma patients upon allergen challenge and increased mRNA levels of CB1 in peripheral blood mononuclear cells and tonsils from atopic and asthma patients have been reported [Citation38,Citation39], suggesting that the ECS might play an important role in the pathogenesis of asthma in humans. We have recently shown that the synthetic cannabinoid WIN55212–2 induces human tolerogenic DCs with the capacity of generating highly suppressive regulatory T (Treg) cells by mechanisms depending on autophagy induction and metabolic reprogramming [Citation40]. Human T cells, B cells and different subsets of DCs express functional CBRs [Citation39]. WIN55212–2 also suppress T cell responses and promote Treg cells in human tonsils [Citation41], impair inflammatory properties in human macrophages [Citation42] and prevent peanut-allergic sensitization by promoting the generation of functional Treg cells [Citation43]. The generation and maintenance of functional Treg cells plays a key role in the restoration of healthy immune responses in the airways of asthma patients and other inflammatory diseases [Citation8,Citation44]. Remarkably, WIN55212–2 restores rhinovirus-induced epithelial barrier disruption [Citation45], suggesting that this synthetic cannabinoid also directly acts on human BECs favoring their restoration upon viral infections, which together with allergic sensitization constitute a major risk factor for asthma development. This barrier protective effects and its immunomodulatory and anti-inflammatory properties, point out WIN55212–2 as a potential suitable cannabinoid for asthma treatment.

2. Expert opinion

Compelling experimental evidence both in animal models and humans demonstrates that the ECS plays an important role in the pathophysiology of asthma by regulating immune system cells and different key structural cells, such as smooth muscle cells, endothelial cells, BECs, fibroblasts and neurons in the airways. There is a potential scenario for cannabinoids or molecules targeting ECS as novel therapeutic interventions in asthma, but a better understanding of the role played by specific cannabinoid ligands and CBRs on the different cell types is required. The generation or modification of already existing synthetic cannabinoids able to target specific CBRs in the periphery avoiding CNS-mediated psychotropic effects might well provide the suitable framework for the development of more selective cannabinoid-based therapeutic interventions for asthma patients. At this regard, several compounds targeting CB2, peripherally restricted CB1 and endocannabinoids degrading enzymes have demonstrated to attenuate neuropathic pain with limited side effects [Citation46,Citation47]. Importantly, large-scale clinical trials to determine whether specific cannabinoids might well be safe and effective drugs for asthma treatment are warranted.