Cynthia Kanagaratham1, Yasmeen S El Ansari2, Benjamin F Sallis3, Brianna-Marie A Hollister3, Owen L Lewis3, Samantha C Minnicozzi1, Michiko K Oyoshi1, Rachel Rosen1, Samuel Nurko1, Edda Fiebiger1, Hans C Oettgen4. 1. Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. 2. Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; Institute of Laboratory Medicine, Philipps University Marburg, Germany. 3. Department of Pediatrics, Boston Children's Hospital, Boston, Mass. 4. Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass. Electronic address: hans.oettgen@childrens.harvard.edu.
Abstract
BACKGROUND: Patients with eosinophilic esophagitis have increased numbers of mucosal mast cells. Administration of the proton pump inhibitor omeprazole can reduce both esophageal mast cell and eosinophil numbers and attenuate type 2 inflammation in these subjects. OBJECTIVE: Given that maintenance of an acidic environment within granules is important for mast cell homeostasis, we sought to evaluate the effects of omeprazole on mast cell functions including development, IgE:FcεRI-mediated activation, and responses to food allergen. METHODS: Mast cell degranulation, cytokine secretion, and early signaling events in the FcεRI pathway, including protein kinase phosphorylation and Ca2+ flux, were measured after IgE crosslinking in murine bone marrow-derived mast cells and human cord blood-derived mast cells. The effects of omeprazole on these responses were investigated as was its impact on mast cell-dependent anaphylaxis and food allergy phenotypes in vivo. RESULTS: Murine and human mast cells treated with omeprazole exhibited diminished degranulation and release of cytokines and histamine in response to allergen. In murine mast cells, phosphorylation of protein kinases, ERK and SYK, was decreased. Differentiation of mast cells from bone marrow progenitors was also inhibited. IgE-mediated passive anaphylaxis was blunted in mice treated with omeprazole as was allergen-induced mast cell expansion and mast cell activation in the intestine in a model of food allergy. CONCLUSIONS: Our findings suggest that omeprazole targets pathways important for the differentiation and activation of murine mast cells and for the manifestations of food allergy and anaphylaxis.
BACKGROUND:Patients with eosinophilic esophagitis have increased numbers of mucosal mast cells. Administration of the proton pump inhibitor omeprazole can reduce both esophageal mast cell and eosinophil numbers and attenuate type 2 inflammation in these subjects. OBJECTIVE: Given that maintenance of an acidic environment within granules is important for mast cell homeostasis, we sought to evaluate the effects of omeprazole on mast cell functions including development, IgE:FcεRI-mediated activation, and responses to food allergen. METHODS: Mast cell degranulation, cytokine secretion, and early signaling events in the FcεRI pathway, including protein kinase phosphorylation and Ca2+ flux, were measured after IgE crosslinking in murine bone marrow-derived mast cells and human cord blood-derived mast cells. The effects of omeprazole on these responses were investigated as was its impact on mast cell-dependent anaphylaxis and food allergy phenotypes in vivo. RESULTS:Murine and human mast cells treated with omeprazole exhibited diminished degranulation and release of cytokines and histamine in response to allergen. In murine mast cells, phosphorylation of protein kinases, ERK and SYK, was decreased. Differentiation of mast cells from bone marrow progenitors was also inhibited. IgE-mediated passive anaphylaxis was blunted in mice treated with omeprazole as was allergen-induced mast cell expansion and mast cell activation in the intestine in a model of food allergy. CONCLUSIONS: Our findings suggest that omeprazole targets pathways important for the differentiation and activation of murine mast cells and for the manifestations of food allergy and anaphylaxis.
Authors: James P Franciosi; Edward B Mougey; Evan S Dellon; Carolina Gutierrez-Junquera; Sonia Fernandez-Fernandez; Rajitha D Venkatesh; Sandeep K Gupta Journal: J Asthma Allergy Date: 2022-02-26