α-Cyperone targets the PAK1-JNK/NF-κB axis to modulate dendritic cells maturation and Th2/Th9 differentiation in an asthma model

Abstract

Asthma is a common chronic airway inflammatory disease affecting millions of patients worldwide, and its treatment remains a clinical challenge. A variety of immune cells, cytokines and inflammatory mediators are associated with asthmatic pathogenesis. The α-Cyperone (CYP) is the active ingredient of Cyperus rotundus L., which exhibits significant anti-inflammatory effects in numerous diseases. However, whether and how CYP plays a role in allergic asthma has not yet been reported. It was found that CYP inhibits airway inflammation and mucus hypersecretion in a mouse allergic asthma model by reducing the proportion of mature dendritic cells (DCs) and the differentiation of Th2 and Th9 cells in lung tissue and mediastinal lymph nodes. Furthermore, CYP inhibits DCs maturation via the PAK1-JNK/nuclear factor-κB (NF-κB) pathway, thereby attenuating subsequent Th2 and Th9 cell differentiation. Moreover, it was found that IL-33 can promote the differentiation of naïve T cells into Th2/Th9 by activating PAK1-JNK/NF-κB signaling. CYP decreases this IL-33-induced Th2/Th9 differentiation by inhibiting the PAK1-JNK/NF-κB axis. The computational analysis indicates that CYP binds to the PAK1 protein at Ser144 that verified by Biacore surface plasmon resonance analyzes and kinase activity testing. Taken together, the present study demonstrated that CYP improves allergic asthma by targeting PAK1 to inhibit the PAK1-JNK/NF-κB pathway.