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

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.