Datura Metel L. Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis and Inhibits Inflammatory Cytokines Production through TLR7/8-MyD88-NF-κB-NLRP3 Inflammasome Pathway.

Bing-You Yang,Wei Guan,Hai-Xue Kuang,Yan-Gang Cheng,Yan Liu,Shuang Guo,Jin-Yan Tan,Yuan Liu

doi:10.3390/molecules24112157

Abstract

Background: Psoriasis is a chronic, immune-mediated inflammatory skin disease, and the inflammatory response plays an important role in its development and progression. Datura metel L. is a traditional Chinese medicine that exhibited a significant therapeutic effect on psoriasis in our previous study due to its remarkable anti-inflammatory effect. Meanwhile, the mechanism underlying its effects on psoriasis is still unclear. Methods: An imiquimod-induced psoriasis-like dermatitis mouse model was constructed to evaluate the protective effect of the effective part of Datura metel L. (EPD), which was verified by evaluations of the Psoriasis Area and Severity Index (PASI) score. Hematoxylin and eosin (H&E) staining, immunohistochemical examination, enzyme-linked immunosorbent assay (ELISA), and Western blot were used to measure the inflammatory cytokines and the protein expression associated with the Toll-like receptor 7– myeloid differentiation primary response gene 88–nuclear Factor-κB–nucleotide-binding oligomerization domain (Nod)-like receptor family pyrin domain-containing 3 (TLR7/8–MyD88–NF-κB–NLRP3) inflammasome pathway. Results: EPD significantly decreased the PASI, reduced epidermal thickness, and decreased the proliferation and differentiation of epidermal cells in psoriasis-like dermatitis C57BL/6 mice induced by imiquimod (IMQ). Furthermore, EPD reduced the infiltration of CD3+ cells to psoriatic lesions, as well as ameliorated the elevations of intercellular adhesion molecule 1 (ICAM-1) and inhibited the production of imiquimod-induced inflammatory cytokines, including IL-1β, IL-2, IL-6, IL-10, IL-12, IL-17, IL-22, IL-23, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP-1), and interferon-γ (IFN-γ). Besides, EPD decreased the imiquimod-induced expression levels of TLR7, TLR8, TRAF6, MyD88, p-IKKα, p-IKBα, p-NF-κB, NLRP3, apoptosis-associated speck-like protein contained a caspase recruitment domain (ASC), cysteinyl aspartate specific proteinase 1 (caspase-1), and IL-1β. Conclusion: This study demonstrated that EPD exhibited a protective effect on an imiquimod-induced psoriasis mice model by inhibiting the inflammatory response, which might be ascribed to the inhibition of the TLR7/8–MyD88–NF-κb–NLRP3 inflammasome pathway.

Highlights

Psoriasis, a chronic inflammatory skin condition, is commonly considered to be induced by multiple environmental and genetic factors
This study demonstrated that effective part of Datura metel L. (EPD) exhibited a protective effect on an imiquimod-induced psoriasis mice model by inhibiting the inflammatory response, which might be ascribed to the inhibition of the TLR7/8–myeloid differentiation primary response gene 88 (MyD88)–NF-κb–NLRP3 inflammasome pathway
For investigating the protective effects of EPD on psoriasis mice induced by imiquimod (IMQ), EPD was orally administrated once daily 4 h after modeling for seven consecutive days, and the severity of lesions on the back skin were scored on the basis of Psoriasis Area and Severity Index (PASI)

Summary

Introduction

A chronic inflammatory skin condition, is commonly considered to be induced by multiple environmental and genetic factors. TLR signaling involved the recruitment of adaptor proteins; TLR7/8 were the main TLRs which induced the recruitment of myeloid differentiation primary response gene 88 (MyD88); the MyD88-dependent pathway activated nuclear Factor-κB (NF-κB), and this caused various inflammatory cytokines to extensively express, as well as provided the positive feedback effect on the TLR7/8-MyD88-NF-κB signaling, resulting in the persistent inflammation [2,12]. As one of the downstream factors of TLRs, the nucleotide-binding oligomerization domain (Nod)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic macromolecular complex and consists of NLRP3, cysteinyl aspartate specific proteinase 1 (caspase-1), and apoptosis-associated speck-like protein contained a caspase recruitment domain (ASC). EPD decreased the imiquimod-induced expression levels of TLR7, TLR8, TRAF6, MyD88, p-IKKα, p-IKBα, p-NF-κB, NLRP3, apoptosis-associated speck-like protein contained a caspase recruitment domain (ASC), cysteinyl aspartate specific proteinase 1 (caspase-1), and IL-1β

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