Metabolic Regulation of Mast Cell Regranulation

Abstract

Mast cells (MCs) are long-lived hematopoietic cells located within tissues. These cells are densely packed with granules containing preformed bioactive components that are released within seconds to minutes upon activation in a process called degranulation. MCs have beneficial roles in pathogen clearance and wound healing but are most widely associated with their deleterious effects in allergic diseases. Importantly, MCs have been shown to reform granules following degranulation in vitro. This capacity for multiple cycles of degranulation and regranulation is thought to contribute to chronic allergic diseases such as asthma and atopic dermatitis, however, MC regranulation has not been previously demonstrated in vivo. Additionally, how MCs regulate regranulation has not been previously shown. In this study, we demonstrate that following anaphylaxis, peritoneal MCs from mice can undergo regranulation. Additionally, using inducible Raptor knockout mice, we show that mTORC1, a well-known mediator of cellular metabolism, is necessary for MC regranulation in vitro and in vivo. Using a microarray approach, we determined that mTORC1 activity is regulated by Slc37a2. This glucose-6-phosphate transporter is necessary for increased glucose-6-phosphate and ATP concentrations during regranulation, two upstream signals of mTOR. Additionally, Scl37a2 was found localized to endosomes during regranulation, where it concentrated extracellular cargo which are trafficked into newly formed granules. Thus, MC regranulation is regulated by a metabolic reprogramming that requires the interaction of the glucose-6-phosphate transporter Slc37a2 and the nutrient sensor mTORC1.