TY - JOUR T1 - Cytokine production of alveolar macrophages is decreased by OR2AT4 JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.congress-2021.PA692 VL - 58 IS - suppl 65 SP - PA692 AU - Daniel Weidinger AU - Kaschin Jamal Jameel AU - Desiree Alisch AU - Matthias Ruhe AU - Paul Bürger AU - Simon Rohde AU - Faisal Yusuf AU - Peter Kaufmann AU - Juliane Kronsbein AU - Marcus Peters AU - Nikolaos Giannakis AU - Hanns Hatt AU - Jürgen Knobloch Y1 - 2021/09/05 UR - http://erj.ersjournals.com/content/58/suppl_65/PA692.abstract N2 - Background: Therapies that decelerate the progression of COPD and severe non-type2 asthma are missing. Alveolar macrophages (AM) are key in both pathophysiologies and represent suitable target cells. Promising molecular targets are G-protein coupled receptors. The largest subgroup, the olfactory receptors (OR), are ubiquitously expressed and mediate various cellular processes, but pre-clinical data are lacking.Hypothesis: OR2AT4 signaling interferes with molecular pathologies in AM and could be considered a potential therapeutic target for COPD or non-type2 asthma.Methods: AM were isolated from bronchoalveolar lavages of patients with (suspected) COPD or asthma. OR2AT4 mRNA and protein expression were investigated by western blot, immunocytochemistry and RT-PCR. Downstream signaling was investigated by using specific inhibitors and by calcium imaging. Cytokines were measured in the cell culture supernatants 24h after stimulation by ELISA.Results: Sandalore, a synthetic OR2AT4 agonist, mediates a transient increase of intracellular calcium and induces cAMP. Oxyphenylon (OR2AT4 antagonist), MDL12330A (adenylate cyclase blocker), and removal of extracellular calcium by EGTA reduced the calcium increase. Stimulation of OR2AT4 inhibited baseline IL-8 and LPS-induced IL-6, IL-8, IL-10, CCL2, MMP9, LTA-induced IL-6, IL-8, CCL2, and PGN-induced IL-8 secretion.Conclusion: OR2AT4 interferes with cytokine production induced by bacterial PAMPs possibly via Ca2+/cAMP signaling in AM. OR2AT4 or downstream signaling might be a drug target to reduce inflammation.FootnotesCite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA692.This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only). ER -