Mast cells function as innate sentinels, whose activation protects the host from infection but can also cause pathological inflammation. Intervening in mast cell function can provide new therapeutic targets for unmet clinical needs. An area of growing interest and significant knowledge gaps is the connection between inflammation and depression. These data are bi- directional: depression is common among patients with chronic inflammation, and alleviating inflammation improves depression. Among the literature related to this area is evidence that selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory properties associated with their clinical efficacy. This link prompted us to examine SSRI effects on IgE-mediated mast cell function. We show that several SSRIs can suppress IgE-mediated mast cell degranulation and cytokine secretion in vitro, which may be due to inhibiting purinergic receptors of the P2X family. These results are consistent in vivo, as the SSRI fluoxetine suppressed IgE-mediated anaphylactic shock and plasma cytokine levels. P2X receptors are trimeric, extracellular ATP- gated ion channels expressed on neurons as well as many immune cells, including mast cells. Extracellular ATP is released by IgE-activated mast cells, is elevated in inflamed tissue, and can exacerbate inflammation by activating P2X receptors. Although the importance for P2X receptors in immune function is accepted, much is unknown about purinergic signaling in mast cells, how this is related to allergic disease, and any connection to SSRI therapy. Therefore, this project will test the hypothesis that SSRIs suppress IgE-mediated mast cell activation by inhibiting P2X receptors, preventing purine-mediated exacerbation of the inflammatory response.
Mast cell activation by IgE antibodies is a critical step in allergic inflammation. We find that serotonin-selective reuptake inhibitors (SSRIs) can suppress IgE-induced mast cell responses in vitro and in vivo, possibly through the P2X receptor family. This application will expand our work to human cells and determine the biochemical mechanisms of action.
