New Findings: What is the central question of this study? Does Toll-like receptor 7 (TLR7) have any direct effects on Ca2+-dependent physiological function of tracheal submucosal gland cells? What is the main finding and its importance? TLR7 is co-localized with SERCA2 in tracheal submucosal gland cells and causes a rapid attenuation of acetylcholine (ACh)-induced, Ca2+-dependent ionic currents through the activation of SERCA2-dependent Ca2+ clearance. TLR7 is abundantly expressed in the airways of both swine and healthy human subjects, but is significantly downregulated in chronic obstructive pulmonary disease (COPD) airways. These findings suggest that a dysfunction of TLR7 in COPD removes the brake on ACh-induced serous secretion during viral infections, resulting in prolonged airway hypersecretion, and that it is one of the triggers of COPD exacerbations. Abstract: Airway surface fluids are mainly secreted from submucosal glands (SMGs) and play important roles in the defence of airways via the activation of mucociliary transport. Toll-like receptor 7 (TLR7) recognizes and eliminates single stranded RNA (ssRNA) viruses through the induction of innate immunity. However, there is no obvious connection between TLR7 and mucus secretion, aside from TLR7 recognizing ssRNA viruses, which are often associated with airway hypersecretion in chronic obstructive pulmonary disease (COPD). Here, we investigated whether TLR7 has any direct effects on the Ca2+-dependent physiological function of tracheal SMG cells. Patch-clamp analyses revealed that TLR7 ligand inhibited the acetylcholine (ACh)-induced ionic currents in isolated tracheal SMG cells. Intracellular calcium assays and pharmacological analyses revealed that TLR7 attenuated the transient rises in the intracellular calcium concentration evoked by ACh by activating sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2). Immunofluorescence staining and immunohistochemical staining revealed that TLR7 was co-localized with SERCA2. These findings suggest that the activation of TLR7 during viral infections contributes to the rapid attenuation of ACh-induced ionic currents through an increase in SERCA2-dependent Ca2+ clearance in healthy airway SMG cells. Our study also revealed that TLR7 expression was significantly downregulated in COPD airways. Based on these findings, we speculate that a dysfunction of TLR7 may not only have an adverse effect on the elimination of these viruses but also remove the brake on ACh-induced serous secretion, resulting in prolonged hypersecretion and acting as one of the triggers of COPD exacerbations.
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