Second-Generation H₁-Receptor Antagonists, Mequitazine, Azelastine and Desloratadine Activate Caspase-8, Caspase-3, and Gasdermin E and Induce Cell Death Showing Pyroptotic-Like Features in Macrophages at Excessively High Concentrations

Abstract

Histamine H₁ receptor (H₁R) is expressed in various cells, including neurons, smooth muscle cells, hepatocytes, T and B cells, neutrophils, dendritic cells, monocytes, and macrophages. Antagonists that target the H₁R are used to relieve the symptoms of allergy and inflammation. Here, we examined the inflammation-modulating and cell death-inducing effects of 10 second-generation H₁R antagonists on mouse intraperitoneal macrophages, which include ketotifen, mequitazine, azelastine, oxatomide, epinastine, bepotastine, fexofenadine, loratadine, levocetirizine, and desloratadine, to assess an anticipated adverse reaction. Three of these antagonists, namely, mequitazine, azelastine, and desloratadine, induced the secretion of interleukin-1α (IL-1α), a marker of pyroptosis and an inflammatory cytokine, from the macrophages at excessively high concentrations, while reducing the secretion of another inflammatory cytokine, IL-6. We found that the macrophages treated with the 3 antagonists showed pyroptotic-like, but not apoptotic-like, morphology and died. Western blotting analysis revealed that caspase-8, caspase-3, and gasdermin E (GSDME), but not gasdermin D, were cleaved and activated in the macrophages. These results suggest that second-generation H₁R antagonists such as mequitazine, azelastine, and desloratadine induce pyroptotic-like cell death accompanied by caspase-8, caspase-3, and GSDME activation in macrophages.