Neurogranin negatively regulates gene expression and proinflammatory mediator release in allergen-activated mast cells

Mast cells are critical players in the maladaptive immune responses underlying biphasic reactions in allergic inflammation. Neurogranin (Ng) is an IQ domain–containing protein that sequesters Calmodulin under low [Ca2+] and negatively regulates calmodulin-mediated signaling such as calcineurin activation, in addition to downstream inflammatory responses. Previously described as brain specific, Ng has recently been identified in the spleen, bone marrow, and B lymphocytes, highlighting the need to investigate its negative regulatory role in other proinflammatory contexts. Here, we sought to determine the role of Ng in allergen-activated mast cells, to better understand the negative regulatory mechanisms that can potentially be exploited to help alleviate the severity of allergic inflammation. Using bone marrow–derived mast cells from wild-type (Nrgn+/+) and heterozygous (Nrgn+/−) mice, we identified that Ng is present in mast cells. It was determined that although Ng did not influence the development of mature mast cells or the extent of early-phase inflammation, a reduction in Ng significantly increased gene expression of IL6 and IL13, which was coupled with an increase in release of IL-6, IL-13, TNF, CCL1, CCL2, and CCL3. Together, this is the first study to identify Ng in mast cells, in addition to positioning its role as a negative regulator of mast cell responses following allergen activation. These data highlight the need for future research to further elucidate the role of Ng in IgE-mediated mast cell activation to better understand the regulatory mechanisms of these inflammatory cells in mast cell–driven normal and pathological contexts.