CKBA

Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3-O-cyclohexanecarbonyl-11-keto-β-boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)-induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA-seq analysis revealed that CKBA downregulated the extracellular signal-regulated kinase (ERK) signaling in BM-derived mast cells activated by anti-2,4-dinitrophenol/2,4-dinitrophenol-human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t-butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD.

Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer's disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD.