Late Breaking Abstract - Antagonizing COVID19-induced GPR4 alleviates lung and kidney injury

GPR4 is activated by acidosis in inflammation and hypoxia. COPD and bronchiectasis patients have reduced exhaled breath pH values around pH 7.1 suggesting disease-relevance of acidosis. GPR4 is highly expressed in lungs, where it regulates vascular permeability, leukocyte infiltration, and inflammatory response. GPR4 inhibition has thus been proposed to rescue COVID19 features incl. metabolic and respiratory acidosis, hyperinflammation, vessel leakage and edema formation. Additionally, GPR4 KO lowers blood pressure and enhances insulin sensitivity, both beneficial to COVID19 high-risk population. Here we show that GPR4 antagonism rescues edema, cytokine storm and leukocyte recruitment in experimental COPD-exacerbation and ARDS models. Additionally, it reduces kidney damage in an ischemic acute kidney injury model. Cellularly, GPR4 is highly expressed in activated Goblet cells of chronic lung disease patients and induced by IL1b and IL13 in human organotypic cultures. Its inhibition reduces inflammatory burden incl. mucus production. GPR4 is expressed in endothelia of diseased lungs, where it contributes to leukocyte recruitment, and in primary lung macrophages, where its inhibition reduces inflammatory response in a dose- and pH-dependent manner. Finally, RNA from human nasal swabs for Sars-Cov-2 diagnosis reveal correlation between GPR4 expression at test time and severity of COVID-19 severity at later stage. Altogether our data suggest that GPR4 antagonists may serve to reduce injury severity in lungs and kidneys of COVID19 patients. Additionally, early correlation between GPR4 expression in nasal swabs and future disease severity suggest potential as early predictive outcome biomarker.