Wednesday, April 2, 2025
4/2/2025
Prostaglandin E2-Dependent Control of a Mast Cell IL-33/ST2 Pathway in Asthma - Abstract This proposal focuses on the potential role of mast cells in the control of type 2 immunopathology (T2I) elicited by IL-33, a principal effector cytokine involved in the onset and persistence of upper and lower airway inflammation. Preliminary studies demonstrate that mast cells are required to drive type 2 inflammation when the levels of prostaglandin E2 (PGE2) are reduced, but paradoxically shift to an anti-inflammatory role when PGE2 levels are sufficient. We have now found that mast cells are necessary to control the production of soluble ST2 (sST2), a decoy receptor that binds IL-33 and limits its bioavailability in vivo. Moreover, PGE2 upregulates the expression of sST2 while downregulating the expression of ST2L, the cell surface receptor for IL-33. Aim 1 will determine the mechanism(s) by which mast cells protect the lung from IL-33-induced T2I, and identify the mast cell subsets that are responsible. Aim 2 will determine the receptors and molecular mechanisms by which PGE2 alters the expressions of sST2 and ST2L, and Aim 3 will verify the importance of these mechanisms in vivo. The studies have strong translational implications for the pathophysiology of respiratory T2I, and could point the way toward the development of logical therapeutic strategies for asthma and chronic sinus disease.
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