Abstract This Project focuses on the mechanisms by which structural cell-derived “level 1” innate type 2 cytokines interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) drive the production of pathogenic eicosanoids (particularly prostaglandin (PG)D2 and thromboxane (TX)A2)) by mast cells (MCs) in the respiratory mucosa, and by which those eicosanoids in turn amplify inflammation secondary to the innate type 2 immune system through effects on blood-born effector cells. Impaired PGE2 production and/or receptor function permits the initiating events to drive a feed forward loop, resulting in persistent respiratory mucosal inflammation, hyperplastic eosinophilic sinusitis, recurrent nasal polyposis, and severe asthma that characterize AERD. The central hypothesis is that respiratory inflammation is controlled by a balance between the effects of inductive (IL-33 and TSLP) and suppressive (PGE2) factors derived from persistently activated structural cells. AERD results from imbalances in this system that lower the threshold for the activation of MCs and other effector cells, resulting in overproduction of pathogenic eicosanoids (PGs, cysteinyl leukotrienes (cysLTs), and recruitment and/or activation of eosinophils, basophils, type 2 innate lymphoid cells (ILC2s), other lymphoid populations, and platelet-adherent granulocytes. Aim 1 is to identify the cellular source(s) of IL-33, TSLP, and prostaglandin (PG)E2 in nasal polyps and to determine the extent to which the endogenous cytokines drive MC eicosanoid generation in aspirin exacerbated respiratory disease (AERD). Aim 2 is to identify factors from nasal polyp structural cells that prime local MCs and regulate their transcriptional profile. Aim 3 is to determine the importance of MC and structural cell-derived eicosanoids in driving accumulation and activation of effector cells of innate and adaptive immunity in the respiratory tissue. The data in this Project will be incorporated by Core B with data from Project 2 to build a predictive network model for AERD pathogenesis that will inform all three projects.