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J Exp Med. 2016 Aug 22;213(9):1663-73. doi: 10.1084/jem.20151739. Epub 2016 Aug 15.

Carbonic anhydrase enzymes regulate mast cell-mediated inflammation.

Author information

1
Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103 Department of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
2
Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103 Department of Pediatrics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
3
The Genomics Center, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103 Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
4
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115 Harvard Medical School, Boston, MA 02115.
5
Center for Immunity and Inflammation, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103 Department of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103 mark.siracusa@rutgers.edu.

Abstract

Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. In this study, we show that carbonic anhydrase (Car) enzymes are up-regulated in type 2-associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent mouse mast cell responses and inflammation after Trichinella spiralis infection or the induction of food allergy-like disease. Further, we used CRISPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively, these experiments identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be used to treat mast cell-mediated inflammation.

PMID:
27526715
PMCID:
PMC4995079
DOI:
10.1084/jem.20151739
[Indexed for MEDLINE]
Free PMC Article

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