Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Abstract

Cysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE 4 , the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE 4 that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC 4 synthase (LTC 4 S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE 4 . GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE 4 one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC 4 S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE 4 and of GPR99 may have therapeutic benefits in asthma.C ysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are lipid mediators detected during asthma exacerbations triggered by allergen (1), aspirin (2, 3), and respiratory viruses (4). The cysLTs elicit vascular permeability, inflammation, and bronchoconstriction through three G-protein-coupled receptors. The type 1 cysLT receptor (CysLTR), CysLT 1 R, is the highaffinity receptor for LTD 4 and the dominant CysLTR mediating airway smooth muscle constriction (5-8). The type 2 CysLTR, CysLT 2 R, has prominent effects on the vascular endothelium (9-12) and also elicits bronchial constriction (13,14). LTE 4 , the stable cysLT (15-18), is a weak agonist for CysLT 1 R and CysLT 2 R in transfected cells (5, 19), but elicits airflow obstruction in patients with asthma (20-22). Moreover, LTE 4 has comparable activity to LTC 4 and LTD 4 in eliciting a wheal and flare response in human skin (23), and LTE 4 elicits cutaneous vascular permeability in mice lacking both CysLT 1 R and CysLT 2 R, suggesting the existence of a high-affinity receptor for LTE 4 , which was recently identified as GPR99 (24,25). However, the mechanism by which LTE 4 induces lung pathobiology and the role of GPR99 remain poorly understood.The cysLTs are derived from arachidonate through the serial enzymatic actions of 5-lipoxygenase and leukotriene C 4 synthase (LTC 4 S). LTC 4 , the terminal product of intrac...

The weight of nutrients: kynurenine metabolites in obesity and exercise

“…Inhibits lipolysis in WAT [160]. Involved in retinal neovascularization [161] and cardiac hypertrophy [162] Gpr99 a-ketoglutarate Stimulates LTE4-mediated mucin release in respiratory epithelial cells [163] Gpr109a (PUMA-G/ HM74a)…”

Pro-Resolving Mediator Profiles And 5-Lipoxygenase Activity In Cerebrospinal Fluid Correlate with Disease Severity and Outcome in Adults with Tuberculous Meningitis

“…There was a significant negative correlation between a select group of pro-resolving mediators, 15-epi-LXB 4 , RvD2 n-3 DPA , 22-OH-PD1, MaR1 and 15-epi-LXA 4 , and increasing disease severity (Figure 2C and Supplemental Table 2). In addition, we also observed increased concentrations of LTE 4 , the terminal product in the cysteinyl leukotriene biosynthetic metabolome and that was recently found to be also bioactive (19), with increasing disease severity, although the correlation was not statistically significant after correction for multiple testing (Figure 2C, Supplemental Table 2).…”

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019

“…Histamine (H 1 and H 2 receptors) [94], LTC 4 and LTD 4 [95], PAF [96], PGD 2 [97], IL-1β [98], and IL-13 [99] activate specific receptors on BECs. IL-13 [100] and LTE 4 [101] elicit mucin release from goblet cells. IL-13 is induced in the adipose tissue of obese humans and activates IL-13Rα2 on adipocytes [102].…”