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  • The ability of TKIs in inducing

    2021-07-26

    The ability of TKIs in inducing CRTH2 expression could be related to the c-terminal of CRTH2 receptor that is important molecular determinant in the down-stream signaling cascade activation [20]. This requires further studies to prove it or disprove it. Additionally, further studies are needed to explore which specific tyrosine kinase(s) is involved in the CRTH2 gene expression that is beyond the scope of the current communication. In conclusion, we propose that tyrosine kinase inhibition is a novel mediator of inflammation. In one hand, as we reported earlier, it can attenuate eosinophilic inflammation mediated via CCR3 [14] and on the other hand, as reported herein, it may at least in part be an important factor in inducing CRTH2 dynamics and functionality, and thus potentiating eosinophilic inflammation. If so, this may provide a novel mechanism for the pathophysiology of the neuro-immuno-axis in allergic rhinitis, and open channels for therapeutic modalities aiming at treating inflammatory cells in allergic rhinitis.
    Competing interests
    Acknowledgments This study was supported by fund from CHU de Liege-FIRS, 2014/15.
    Introduction Prostaglandin D2 (PGD2) is a prostaglandin derived from the metabolism of arachidonic MnTBAP Chloride by cyclooxygenases and downstream PGD2 synthases. PGD2 is a pleiotropic molecule that is involved in many different processes such as sleep, regulation of nerve-cell function, reduction of intraocular pressure, modulation of nociception, hormone release, bronchoconstriction, vasodilation and inflammation [1]. In the immune system, PGD2 is mainly produced by mast cells [2] but also, although at lower levels, by other cells like dendritic cells and Th2 lymphocytes [3], [4]. PGD2 is induced in response to local tissue damage and allergic inflammation in diseases such as asthma [5], [6], [7], allergic rhinitis and atopic dermatitis among others [8], [9], [10], [11]. PGD2 binds to three different receptors: the prostaglandin D2 receptor or DP (also known as DP1) [12], the chemoattractant receptor-homologous molecule expressed on Th2 cells or CRTh2 (also known as DP2) [13] and the thromboxane-type prostanoid receptor (TP), although at higher concentrations [14], [15]. Activation of CRTh2 by PGD2 induces a reduction of intracellular cAMP and the mobilization of calcium. It is involved in the chemotaxis of Th2 lymphocytes, eosinophils, mast cells and basophils [16], [17], [18], [19], and inhibits the apoptosis of Th2 lymphocytes [20]. Moreover, CRTh2 activation has a role in the production of IL4, IL5, and IL13 [21] which are cytokines involved in important biological responses like eosinophil recruitment and survival, mucus secretion, airway hyper responsiveness and immunoglobulin E (IgE) production among others. Therefore, molecules that antagonize the mentioned pro-inflammatory PGD2 effects mediated by CRTh2 on key cell types associated with allergic inflammation including basophils, eosinophils, mast cells and Th2 lymphocytes (most relevant T cell population in mild-moderate asthma), would have a potential benefit in asthma and related pathologies like allergic rhinitis and atopic dermatitis. The roles of DP1 and CRTh2 in human asthma have been under debate for several years but recently preclinical and clinical evidences seem to clarify this situation. DP1 mediates both pro and anti-inflammatory effects of PGD2 while CRTh2 mediates mostly proinflammatory effects of this prostaglandin and with the potential that responses mediated by both receptors could be antagonizing each other [22], [23], [24]. Asthma clinical studies of the DP1 antagonist Laropiprant and also of the dual DP1-CRTh2 compound AMG-853 showed no efficacy vs placebo or vs montelukast [25], [26]. So, at present, preclinical and clinical studies are mainly focussed on pure CRTh2 antagonists. Several compounds are currently in clinical trials for asthma, allergic rhinitis and atopic dermatitis. Positive results have been reported for OC-459 in allergic rhinitis and asthma clinical studies. After 28days of 200mg bid OC-459 administration to asthmatic patients, it was observed an improvement in pulmonary function of 7.4% in FEV1, a significant decrease in total IgE levels, a reduction of eosinophils in sputum, a reduction in night time symptoms and an improvement in quality of life. Even with high dosing, CRTh2 antagonism seems to be a MnTBAP Chloride very safe mechanism with no adverse effects associated to it [27], [28], [29]. Further OC-459 studies in eosinophilic asthma patients showed positive results at a dose of 25mg once daily [30].