Histamine 4 Receptor Antagonism modulates TH2 cell function, IL13 production, and lung remodeling in a model of chronic asthma

Abstract

H4R antagonists are anti‐inflammatory in murine models of asthma. Here, we examined the specific ability of H4R to modulate TH2 cell function and the associated downstream effects of Th2 cytokine modulation such as: inflammation, mucus cell hyperplasia, MMP expression and collagen disposition, using a selective H4R antagonist. Mice were sensitized i.p. to ovalbumin in alum followed by repeated challenge with ovalbumin. Lungs were lavaged and tissues collected. Therapeutic treatment resulted in decreased lung TH2 cytokines, IL13 and IL5, and decreased cell influx into the lung. In addition to the reduction of eosinophils, there was a reduction in CD3+ cells. Cultured T cell re‐stimulated with antigen ex‐vivo had reduced production of TH2 cytokines. IL13 dependent markers of lung remodeling such as goblet cell hyperplasia, MMP‐9 expression, and total lung collagen were reduced. Thus, we demonstrate that the anti‐inflammatory properties of H4R antagonists include modulation of TH2 cell function, resulting in a reduction of TH2 derived IL13. Consequently, H4R antagonists reduce cardinal signs of asthma such as inflammation and lung remodeling, suggesting their potential as a novel human therapeutics.