Exploring the Expression and Function of Mechanoreceptors on Human Mast Cells

Abstract

Chronic type 2 inflammatory diseases affect millions of people globally. These diseases exhibit tissue remodeling, where inflammatory cells mediate the breakdown of normal extracellular matrix and deposition of excessive submucosal collagen. Tissue remodeling can prompt mechanoreceptor activation through tissue rigidity or integrin activation from binding extracellular matrix proteins. While mast cell activation has a defining role in type 2 inflammation, the presence and functional role of mast cell mechanoreceptor activation is not explored within the literature. We hypothesized that activation of mechanoreceptors on the surface of mast cells could potentiate degranulation and/or mediator release, thereby contributing to type 2 inflammatory disease. We generated mast cells from circulating progenitors in peripheral human blood, evaluated the expression of diverse mechanoreceptors (mechanosensitive ion channels and integrins) on mast cell surfaces, investigated mechanoreceptor upregulation following cytokine treatment, and demonstrated the capacity for mechanoreceptors to affect mast cell activation. We have found diverse mechanosensor expression on human mast cells, with differential expression depending on mast cell subtype and a stable phenotype unaffected by cytokine treatment. Contrary to our original hypothesis, we found variable effects of mechanosensor stimulation on mast cell activation, with one significant finding in TRPV4 activation attenuating mast cell degranulation and mediator production; however, we have also discovered a potential new role of integrin-mediated lipid mediator production independent of degranulation. Thus, we present our findings of novel perspectives on mast cell functionality via mechanosensing.