FAK inhibitor PF-431396 suppresses IgE-mediated mast cell activation and allergic inflammation in mice

• Published in: Biochemical pharmacology 2021-10, Vol.192, p.114722-114722, Article 114722
• Main Authors: Chen, Jia-Jie, Zhang, Li-Na, Wang, Hui-Na, Xie, Chu-Chu, Li, Wei-Yong, Gao, Pan, Hu, Wan-Zhen, Zhao, Zhen-Fu, Ji, Kunmei
• Format: Article
• Language: English
• Subjects: CaMKII; FAK; FcεRI signaling; Mast cell; PF-431396
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114722

[Display omitted] Mast cells (MCs) initiate and maintain allergic inflammation. Upon being stimulated with immunoglobulin (Ig)E and antigen (Ag), MCs exhibit FcεRI (high-affinity IgE) receptor-mediated degranulation, cytokine secretion, and increased focal adhesion kinase (FAK) activity. The aims of this study were to examine mechanisms of FAK regulation in IgE-mediated MC activation and the effects of FAK inhibition on MC-mediated allergic responses. FAK activity was manipulated with short hairpin RNA (shRNA) knockdown, FAK overexpression, and the FAK inhibitor PF-431396 (PF). Gene expression and kinase activation were analyzed with quantitative molecular biology assays. PF effects were tested in the passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), and allergic conjunctivitis (AC) mouse models. Our results showed that FAK overexpression increased IgE-mediated degranulation and reduced the dexamethasone inhibitory effect on MCs activation. The FAK inhibitor PF diminished MC release of β-hexosaminidase (β-hex), histamine, and inflammatory cytokines, via a mechanism that involves MAPK and NF-κB signaling pathways. CaMKII was identified as a robust FAK-associating protein. Inhibition of CaMKII activation by KN-93 suppressed FAK activity and its downstream pathway. PF attenuated inflammatory responses in our PCA and ASA models, and relieved signs of allergic disease in AC model mice. In conclusions, MC degranulation and production of inflammatory mediators in allergic disease may be consequent to FcεRI crosslinking inducing CaMKII-mediated activation of FAK activity. FAK inhibition may represent a new MC-suppressing treatment strategy for the treatment of allergic diseases.