Beneficial effects of the AT ₂ receptor agonist buloxibutid (C21) against acute alveolar epithelial cell inflammation during anti-viral responses

Aim Activation of the angiotensin II type 2 receptor (AT 2 receptor; encoded by AGTR2 ) has been shown to be beneficial during tissue injury and repair. Therefore, we aimed to investigate the expression of AT 2 receptor in human alveolar type II (ATII) cells, a cell population responsible of lung repair and regeneration and the effect of the AT 2 receptor agonist buloxibutid (also known as C21), in an in vitro model of viral infection using primary ATII cells. Methods We described the expression of AT 2 receptor mRNA using publicly available lung single-cell RNA sequencing datasets. We evaluated the effects of buloxibutid on ATII cell biology at baseline and in response to treatment with double stranded RNA (polyinosinic:polycytidylic acid, a pathogen associated molecular pattern) using MTS cytotoxicity assay, transcriptomic analysis and ELISA. Results We found that buloxibutid was well tolerated by ATII cells under all conditions tested. RNA sequencing demonstrated that ATII cells responded to polyinosinic:polycytidylic acid with induction of a characteristic antiviral innate immune response. Gene set enrichment analysis revealed that buloxibutid caused a significant suppression of polyinosinic:polycytidylic acid-induced pro-inflammatory responses whereas it was without effect on the expression of antiviral genes. Conclusions Our findings suggest that buloxibutid may have therapeutic potential for treatment of respiratory viral pneumonias by limiting excessive pro-inflammatory responses that have the potential to lead to a cytokine storm, while maintaining a protective antiviral response.