Mast cells function as innate sentinels, whose activation protects the host from infection but can also cause pathological inflammation. Therefore, new ways of intervening in mast cell function can benefit unmet clinical needs. A significant knowledge gap in immunology is the connection between inflammation and depression. These data are bi-directional: depression is common among patients with chronic inflammation; anti-inflammatory drugs can improve clinical depression; and anti-depressants have anti- inflammatory effects (1-8). These findings include an association between allergic disease and depression (9, 10). These links prompted us to examine effects of the commonly prescribed anti- depressants, selective serotonin reuptake inhibitors (SSRIs), on IgE-mediated mast cell function. We find that SSRIs suppress IgE- mediated mast cell degranulation and cytokine secretion in vitro and systemic anaphylactic shock in vivo. SSRI effects may be due to inhibiting purinergic receptors of the P2X family - ATP-gated ion channels expressed on neurons and many immune cells, including mast cells (11-17). ATP is rapidly released by IgE-activated mast cells (18), is elevated in inflamed tissues, and exacerbates inflammation by activating P2X receptors (19). Although the importance for P2X receptors in immune function is accepted, little is known about purinergic signaling in mast cells, how this is related to allergic disease, and any connection to SSRI therapy. We recently found that the suppressive effects of the SSRI fluoxetine are absent on mast cells lacking P2X3. Therefore, this project will test the hypothesis that SSRIs suppress IgE-mediated mast cell activation by inhibiting P2X3 function, preventing ATP-mediated exacerbation of allergic inflammation.

Public Health Relevance

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, likely acting by suppressing the P2X3 receptor. This application will expand our work to human cells and a model of human asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI138494-02
Application #
9825511
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dong, Gang
Project Start
2018-11-19
Project End
2020-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298