Journal
JOURNAL OF TRANSLATIONAL MEDICINE
Volume 19, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12967-021-02932-0
Keywords
Mast cells; Fc epsilon RI signaling; c-Fos; Egr1; T-5224
Categories
Funding
- National Natural Science Foundation of China [81571570, 82071806]
- Guangdong Province [2021A1515011140]
- SZU Top Ranking Project [86000000210]
- Shenzhen City [JSGG20200102165803939, JSGG20200225151806035]
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The study demonstrates the involvement of c-Fos in mast cell activation and the potential of the c-Fos/AP1 inhibitor T-5224 in alleviating IgE-mediated allergic responses. This suggests a promising strategy for targeting mast cell activation to treat allergic diseases.
Background: Activator protein-1 (AP1), a c-Fos-JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (Fc epsilon RI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/AP1 inhibitor T-5224 on MCs activation and allergic responses. Methods: In vitro studies were conducted with two MC model systems: rat basophilic leukemia cells (RBLs) and mouse bone marrow derived mast cells (BMMCs). MC degranulation and effector functions were examined with beta-hexosaminidase release and cytokine secretion assays. c-Fos/AP1 was inhibited with T-5224. c-Fos activity was suppressed with short hairpin RNA targeting c-Fos (shFos). In vivo immune responses were evaluated in passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models, as well as in an oxazolone (OXA)-induced model of atopic dermatitis, a common allergic disease. Results: c-Fos expression was elevated transcriptionally and translationally in IgE-stimulated MCs. c-Fos binding of the Egr1 (early growth response 1) promoter upregulated Egr1 transcription, leading to production of interleukin (IL)4. T-5224 reduced Fc epsilon RI-mediated MC degranulation (evidenced by beta-hexosaminidase activity and histamine levels) and diminished EGR1 and IL4 expression. T-5224 attenuated IgE-mediated allergic responses in PCA and ASA models, and it suppressed MC-mediated atopic dermatitis in mice. Conclusion: IgE binding can activate MCs via a c-Fos/Egr1/IL-4 axis. T-5224 suppresses MC activation in vitro and in vivo and thus represents a promising potential strategy for targeting MC activation to treat allergic diseases.
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