Anti-atopic dermatitis effects of Parasenecio auriculatus via simultaneous inhibition of multiple inflammatory pathways
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The treatment of atopic dermatitis (AD) is challenging due toits complex etiology. From epidermal disruption to chronic inflammation,various cells and inflammatory pathways contributeto the progression of AD. As with immunosuppressants, generalinhibition of inflammatory pathways can be effective, but thisapproach is not suitable for long-term treatment due to its sideeffects. This study aimed to identify a plant extract (PE) withanti-inflammatory effects on multiple cell types involved in ADdevelopment and provide relevant mechanistic evidence. Degranulationwas measured in RBL-2H3 cells to screen 30 PEsnative to South Korea. To investigate the anti-inflammatory effectsof Parasenecio auriculatus var. matsumurana Nakai extract (PAE)in AD, production of cytokines and nitric oxide, activation statusof FcεRI and TLR4 signaling, cell-cell junction, and cell viabilitywere evaluated using qRT-PCR, western blotting, confocal microscopy,Griess system, and an MTT assay in RBL-2H3, HEK293,RAW264.7, and HaCaT cells. For in vivo experiments, a DNCBinducedAD mouse model was constructed, and hematoxylinand eosin, periodic acid-Schiff, toluidine blue, and F4/80-stainingwere performed. The chemical constituents of PAE were analyzedby HPLC-MS. By measuring the anti-degranulation effects of 30PEs in RBL-2H3 cells, we found that Paeonia lactiflora Pall., PA,and Rehmannia glutinosa (Gaertn.) Libosch. ex Steud. show aninhibitory activity of more than 50%. Of these, PAE most dramaticallyand consistently suppressed cytokine expression, includingIL-4, IL-9, IL-13, and TNF-α. PAE potently inhibited FcεRI signaling,which mechanistically supports its basophil-stabilizing effects,and PAE downregulated cytokines and NO production in macrophagesvia perturbation of toll-like receptor signaling. Moreover,PAE suppressed cytokine production in keratinocytes and upregulatedthe expression of tight junction molecules ZO-1 and occludin. In a DNCB-induced AD mouse model, the topical applicationof PAE significantly improved atopic index scores, immunecell infiltration, cytokine expression, abnormal activation ofsignaling molecules in FcεRI and TLR signaling, and damagedskin structure compared with dexamethasone. The anti-inflammatoryeffect of PAE was mainly due to integerrimine. Our findingssuggest that PAE could potently inhibit multi-inflammatorycells involved in AD development, synergistically block the propagationof inflammatory responses, and thus alleviate AD symptoms.
Abstract
The treatment of atopic dermatitis (AD) is challenging due toits complex etiology. From epidermal disruption to chronic inflammation,various cells and inflammatory pathways contributeto the progression of AD. As with immunosuppressants, generalinhibition of inflammatory pathways can be effective, but thisapproach is not suitable for long-term treatment due to its sideeffects. This study aimed to identify a plant extract (PE) withanti-inflammatory effects on multiple cell types involved in ADdevelopment and provide relevant mechanistic evidence. Degranulationwas measured in RBL-2H3 cells to screen 30 PEsnative to South Korea. To investigate the anti-inflammatory effectsof Parasenecio auriculatus var. matsumurana Nakai extract (PAE)in AD, production of cytokines and nitric oxide, activation statusof FcεRI and TLR4 signaling, cell-cell junction, and cell viabilitywere evaluated using qRT-PCR, western blotting, confocal microscopy,Griess system, and an MTT assay in RBL-2H3, HEK293,RAW264.7, and HaCaT cells. For in vivo experiments, a DNCBinducedAD mouse model was constructed, and hematoxylinand eosin, periodic acid-Schiff, toluidine blue, and F4/80-stainingwere performed. The chemical constituents of PAE were analyzedby HPLC-MS. By measuring the anti-degranulation effects of 30PEs in RBL-2H3 cells, we found that Paeonia lactiflora Pall., PA,and Rehmannia glutinosa (Gaertn.) Libosch. ex Steud. show aninhibitory activity of more than 50%. Of these, PAE most dramaticallyand consistently suppressed cytokine expression, includingIL-4, IL-9, IL-13, and TNF-α. PAE potently inhibited FcεRI signaling,which mechanistically supports its basophil-stabilizing effects,and PAE downregulated cytokines and NO production in macrophagesvia perturbation of toll-like receptor signaling. Moreover,PAE suppressed cytokine production in keratinocytes and upregulatedthe expression of tight junction molecules ZO-1 and occludin. In a DNCB-induced AD mouse model, the topical applicationof PAE significantly improved atopic index scores, immunecell infiltration, cytokine expression, abnormal activation ofsignaling molecules in FcεRI and TLR signaling, and damagedskin structure compared with dexamethasone. The anti-inflammatoryeffect of PAE was mainly due to integerrimine. Our findingssuggest that PAE could potently inhibit multi-inflammatorycells involved in AD development, synergistically block the propagationof inflammatory responses, and thus alleviate AD symptoms.
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