GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

Abstract

Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a nonuniform etiology. Thus, the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients. To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced subchronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cell line HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein-coupled receptor (GPR) 84 in human tissue. Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known proinflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3α, MIG, RANTES and interleukin (IL)-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was upregulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly upregulated in patients with grade B reflux esophagitis. The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.

Three classes of ligands each bind to distinct sites on the orphan G protein-coupled receptor GPR84

“…Clearly an atomic level structure of GPR84 is not available, but even without such information, mutagenesis studies should now start to help unravel the likely modes of binding of these distinct classes of pharmacological regulators of GPR84. Although the GPR84 antagonist GLPG1205 did not show efficacy in patients suffering from ulcerative colitis 28 there remains considerable interest in targeting GPR84 in conditions that range from reflux esophagitis 43 , via cognitive decline 44 , to neuropathic pain 45 . Greater insights into the biology and pharmacological behaviour of ligands at GPR84 will assist in efforts to do so.…”

Global analysis of glycoproteins identifies markers of endotoxin tolerant monocytes and GPR84 as a modulator of TNFα expression

“…IL12 p40, IL-8 and TNFα. Therefore, medium-chain FFAs might link fatty acid metabolism to immunological regulation and inflammatory diseases 69 , 70 . Capric acid stimulation after the initial LPS treatment led to slightly increased TNFα mRNA expression in response to a subsequent LPS stimulus in monocytes and to restored TNFα mRNA expression in tolerant THP-1 cells, comparable to naïve cells.…”

Evaluating the Multitarget Effects of Combinations through Multistep Clustering of Pharmacological Data: the Example of the Commercial Preparation Iberogast

“…Potent anti-inflammatory effects have been shown for STW 5 throughout the gastrointestinal tract, both in vitro and in vivo . Starting at the esophagus, where STW 5 largely attenuated reflux esophagitis in acute and sub-chronic settings 20 , 22 . In the stomach, STW 5 prevented indomethacin-induced inflammation as confirmed by the reduction of leukotriene concentrations, ulcer indices, and prevention of histologically assessed tissue damage.…”