Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R Agonists

Abstract

BackgroundBitter-taste receptors (TAS2Rs) are involved in airway relaxation but are also expressed in human blood leukocytes. We studied TAS2R expression and the effects of TAS2R agonists on the lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs).MethodsLung macrophages were isolated from patients undergoing surgery for carcinoma. We used RT-qPCR to measure transcripts of 16 TAS2Rs (TAS2Rs 3/4/5/7/8/9/10/14/19/20/31/38/39/43/45 and 46) in unstimulated and LPS-stimulated (10 ng.mL–1) LMs. The macrophages were also incubated with TAS2R agonists for 24 h. Supernatant levels of the cytokines TNF-α, CCL3, CXCL8 and IL-10 were measured using ELISAs.ResultsThe transcripts of all 16 TAS2Rs were detected in macrophages. The addition of LPS led to an increase in the expression of most TAS2Rs, which was significant for TAS2R7 and 38. Although the promiscuous TAS2R agonists, quinine and denatonium, inhibited the LPS-induced release of TNF-α, CCL3 and CXCL8, diphenidol was inactive. Partially selective agonists (dapsone, colchicine, strychnine, and chloroquine) and selective agonists [erythromycin (TAS2R10), phenanthroline (TAS2R5), ofloxacin (TAS2R9), and carisoprodol (TAS2R14)] also suppressed the LPS-induced cytokine release. In contrast, two other agonists [sodium cromoglycate (TAS2R20) and saccharin (TAS2R31 and 43)] were inactive. TAS2R agonists suppressed IL-10 production – suggesting that this anti-inflammatory cytokine is not involved in the inhibition of cytokine production.ConclusionHuman LMs expressed TAS2Rs. Experiments with TAS2R agonists’ suggested the involvement of TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39 and 40 in the inhibition of cytokine production. TAS2Rs may constitute new drug targets in inflammatory obstructive lung disease.

Existing bitter medicines for fighting 2019‐nCoV‐associated infectious diseases

“…Indeed, we found that TAS2R10 may help prevent a cytokine storm because it can regulate natural killer cell‐mediated cytotoxicity, chemokine signaling pathways, T cell receptor signaling pathways, TNF signaling pathways, and others (Figure 3). A recent report confirmed our results that TAS2R members 3, 4, 5, 9, 10, 14, 30, 39, and 40 were involved in the inhibition of cytokine production, such as TNF‐α, CCL3, and CXCL8, in human lung macrophages 49 . It reported that quinine, denatonium, dapsone, colchicine, strychnine, chloroquine, erythromycin phenanthroline, ofloxacin, and carisoprodol worked in this inhibition.…”

Clinical Role of Extraoral Bitter Taste Receptors

“…More importantly, TAS2Rs mediated significant inhibition of the release of histamine and PGD2 from IgE-receptor-activated primary human mast cells, which suggests that TAS2R receptors may mediate anti-inflammatory responses. TAS2R expression and the effects of TAS2R agonists on lipopolysaccharide (LPS)-induced cytokine release in human lung macrophages (LMs) were studied by Grassin-Delyle et al [ 36 ]. They found that 16 TAS2Rs are expressed in human LMs with the most abundant transcripts being of TAS2R8 , 14 , 19 , 39 and 46 .…”

Immune Modulation as a Therapeutic Option During the SARS-CoV-2 Outbreak: The Case for Antimalarial Aminoquinolines

“…CQ is a broad-spectrum agonist of bitter taste receptors (TAS2R), a family of G-protein receptors expressed in lungs (airway smooth muscle, airway epithelial cells, lung macrophages, mast cells) and leukocytes, notably lymphocytes, innate lymphoid cells, and monocytes. TAS2R stimulation induces defense mechanisms such as an increase in NO (nitric oxide) production, stimulating mucociliary clearance and exerting antibacterial, anti-inflammatory and muscle relaxant effects ( 53 – 55 ).…”

“…Deacidification of intracellular organelles is not the only immunomodulatory mechanism of CQ. Extragustatory TAS2R stimulation exerts anti-inflammatory properties and bronchodilator activities, and CQ is a TAS2R agonist ( 53 – 55 ). TAS2R stimulation in lung macrophages exposed to CQ significantly inhibited LPS-mediated production of TNFα, CCL3 (C-C motif chemokine ligand 3) and CXCL8 (C-X-C motif chemokine ligand 8), but also of the regulatory cytokine IL-10, suggesting that, at least in this macrophage population, inhibition of the proinflammatory cytokines was not related to IL-10 overexpression ( 55 ).…”