Dataset Information

Tranilast Directly Targets NLRP3 to Protect Melanocytes From Keratinocyte-Derived IL-1? Under Oxidative Stress.

ABSTRACT: The activation of NLRP3 inflammasome-IL-1? pathway in keratinocytes contributes to the melanocyte death via autoimmunity-dependent manner in vitiligo. As a safe small-compound drug employed frequently in clinic, tranilast (TR) is newly reported to block the activation of NLRP3 inflammasome in macrophage. Nevertheless, whether keratinocyte-derived IL-1? damages melanocytes in an autoimmunity-independent way and whether TR could ameliorate the melanocyte damage via inhibiting the NLRP3-IL-1? pathway in keratinocyte still are not clear. In the present study, we initially found that TR could impede the secretion of IL-1? from keratinocytes by interfering the NLRP3 oligomerization. More importantly, we illustrated that TR could decrease the melanocyte apoptosis, improve the melanogenesis, and have the capacity to optimize the melanosome translocation by abolishing the keratinocyte-derived IL-1?. Additionally, TR could mitigate the secretion of inflammatory cytokines such as IL-6, IL-8, TNF-?, and IL-18 in keratinocytes under oxidative stress. In short, our data indicate that IL-1? plays detrimental roles in the melanocyte survival, melanogenesis, melanosome translocation and the secretion of inflammatory cytokines, and TR could be a promising therapeutic strategy in vitiligo by attenuating the keratinocyte-derived IL-1? under oxidative stress.

SUBMITTER: Zhuang T

PROVIDER: S-EPMC7365842 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tranilast Directly Targets NLRP3 to Protect Melanocytes From Keratinocyte-Derived IL-1β Under Oxidative Stress.

Zhuang Tongtian T Li Shuli S Yi Xiuli X Guo Sen S Wang Yinghan Y Chen Jianru J Liu Ling L Jian Zhe Z Gao Tianwen T Kang Pan P Li Chunying C

Frontiers in cell and developmental biology 20200710

The activation of NLRP3 inflammasome-IL-1β pathway in keratinocytes contributes to the melanocyte death via autoimmunity-dependent manner in vitiligo. As a safe small-compound drug employed frequently in clinic, tranilast (TR) is newly reported to block the activation of NLRP3 inflammasome in macrophage. Nevertheless, whether keratinocyte-derived IL-1β damages melanocytes in an autoimmunity-independent way and whether TR could ameliorate the melanocyte damage via inhibiting the NLRP3-IL-1β pathw ...[more]

PMID: 32754591

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Project description:Background Aberrant activation of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP3 ubiquitination blunts the assembly and activation of the NLRP3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low-density lipoprotein receptor- or apolipoprotein E-deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP3 ubiquitination. We showed that tranilast restricted NLRP3 oligomerization and inhibited NLRP3 inflammasome assembly. Tranilast markedly suppressed NLRP3 inflammasome activation in low-density lipoprotein receptor- and apolipoprotein E-deficient macrophages. Through reconstitution of the NLRP3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP3 inflammasome activation. By adopting different regimens for tranilast treatment of low-density lipoprotein receptor- and apolipoprotein E-deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP3 ubiquitination, blunts the assembly and activation of the NLRP3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low-density lipoprotein receptor- and apolipoprotein E-deficient mice.

Dataset Information

Tranilast Directly Targets NLRP3 to Protect Melanocytes From Keratinocyte-Derived IL-1? Under Oxidative Stress.

Publications

Tranilast Directly Targets NLRP3 to Protect Melanocytes From Keratinocyte-Derived IL-1β Under Oxidative Stress.

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