Synergistic mucus secretion by histamine and IL-4 through TMEM16A in airway epithelium

Abstract

Histamine is an important mediator of allergic reactions, and mucus hypersecretion is a major allergic symptom. However, the direct effect of histamine on mucus secretion from airway mucosal epithelia has not been clearly demonstrated. TMEM16A is a Ca-activated chloride channel, and it is closely related to fluid secretion in airway mucosal epithelia. We investigated whether histamine directly induces fluid secretion from epithelial cells or submucosal glands (SMG) and mechanisms related, therewith, in allergic airway diseases. In pig airway tissues from the nose or trachea, histamine was a potent secretagogue that directly induced strong responses. However, gland secretion from human nasal tissue was not induced by histamine, even in allergic rhinitis patients. Histamine type 1 receptor (H1R) and histamine type 2 receptor (H2R) were not noted in SMG by in situ hybridization. Cultured primary human nasal epithelial (NHE) cells were used for the measurement of short-circuit current changes with the Ussing chamber. Histamine-induced slight responses of anion secretions under normal conditions. The response was enhanced by IL-4 stimulation through TMEM16A, which might be related to fluid hypersecretion in allergic rhinitis. Pretreatment with IL-4 augmented the histamine response that was suppressed by a TMEM16A inhibitor. TMEM16A expression was enhanced by 24-h treatment of IL-4 in human nasal epithelial cells. The expression of TMEM16A was significantly elevated in an allergic rhinitis group, compared with a control group. We elucidated histamine-induced fluid secretions in synergy with IL-4 through TMEM16A in the human airway epithelium. In addition, we observed species differences between pigs and humans in terms of gland secretion of histamine.

Pharmacological Inhibition and Activation of the Ca2+ Activated Cl− Channel TMEM16A

“…Because asthma appears to be a common problem also in patients with CF [12], therapeutic activation of TMEM16A could trigger bronchoconstriction in CF patients. Activation of TMEM16A could also trigger mucus release and enhance airway mucus plugging [3,5,13,14].…”

Calcium-Activated Chloride Channel ANO1/TMEM16A: Regulation of Expression and Signaling

“…This review summarizes the current knowledge of mechanisms governing the regulation of ANO1 expression and ANO1-induced intracellular signaling. (Table 1) Most notably, ANO1 expression is increased in response to several interleukins including IL-4 in bronchial epithelial cells (Caputo et al, 2008;Caci et al, 2015) and human nasal epithelial cells (Kang et al, 2017), IL-6 in pancreatic acinar cells (Wang et al, 2020), and IL-13 in human bronchial epithelial cells (Lin et al, 2015;Qin et al, 2016), human nasal polyp epithelial cells and human esophageal keratinocytes (Vanoni et al, 2020). Epidermal growth factor (EGF) promotes ANO1 expression in colonic epithelial cancer cells (Mroz and Keely, 2012) and in breast cancer cells (Wang et al, 2019).…”

Luteolin Attenuates Allergic Nasal Inflammation via Inhibition of Interleukin-4 in an Allergic Rhinitis Mouse Model and Peripheral Blood From Human Subjects With Allergic Rhinitis

“…Mucus hyper-production is a main allergic reaction. IL-4 could enhance the effect of histamine-induced mucus hyper-secretion in allergic responses (Babina et al, 2016;Kang et al, 2017). IL-4 promotes immunoglobulin production and isotype switching by B cells (Wu and Scheerens, 2014;Robinson et al, 2017).…”