| Title: |
A SPLUNC1 Peptidomimetic Inhibits Orai1 and Reduces Inflammation in a Murine Allergic Asthma Model. |
| Authors: |
Wrennall, Joe A., Ahmad, Saira, Worthington, Erin N., Tongde Wu, Goriounova, Alexandra S., Voeller, Alexis S., Stewart, Ian E., Ghosh, Arunava, Krajewski, Krzysztof, Tilley, Steven L., Hickey, Anthony J., Flori Sassano, M., Tarran, Robert |
| Source: |
American Journal of Respiratory Cell & Molecular Biology; Mar2022, Vol. 66 Issue 3, p271-282, 12p |
| Subject Terms: |
PEPTIDOMIMETICS, ASTHMA, INFLAMMATION, CELL membranes, EPITHELIAL cells, ASTHMATICS |
| Abstract: |
Orai1 is a plasma membrane Ca2+ channel that mediates storeoperated Ca2+entry (SOCE) and regulates inflammation. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is an asthma gene modifier that inhibits Orai1 and SOCE via its C-terminal α6 region. SPLUNC1 levels are diminished in asthma patient airways. Thus, we hypothesized that inhaled α6 peptidomimetics could inhibit Orai1 and reduce airway inflammation in a murine asthma model. To evaluate α6–Orai1 interactions, we used fluorescent assays to measure Ca2+ signaling, Forster resonance € energy transfer, fluorescent recovery after photobleaching, immunostaining, total internal reflection microscopy, and Western blotting. To test whether a6 peptidomimetics inhibited SOCE and decreased inflammation in vivo, wild-type and SPLUNC12/2 mice were exposed to house dust mite (HDM) extract with or without a6 peptide. We also performed nebulization, jet milling, and scanning electron microscopy to evaluate α6 for inhalation. SPLUNC12/2 mice had an exaggerated response to HDM. In BAL-derived immune cells, Orai1 levels increased after HDM exposure in SPLUNC12/2 but not wild-type mice. Inhaled α6 reduced Orai1 levels in mice regardless of genotype. In HDM-exposed mice, α6 dosedependently reduced eosinophilia and neutrophilia. In vitro, α6 inhibited SOCE in multiple immune cell types, and α6 could be nebulized or jet milled without loss of function. These data suggest that α6 peptidomimetics may be a novel, effective antiinflammatory therapy for patients with asthm [ABSTRACT FROM AUTHOR] |
|
Copyright of American Journal of Respiratory Cell & Molecular Biology is the property of American Thoracic Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
