Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo

Li, Shuli; Kang, Pan; Zhang, Weigang; Jian, Zhe; Zhang, Qian; Yi, Xiuli; Guo, Sen; Guo, Weinan; Shi, Qiong; Li, Bing; He, Yide; Song, P.; Liu, Ling; Li, Kai; Wang, Gang; Gao, Tianwen; Li, Chunying

doi:10.1016/j.jaci.2019.10.036

Cited by 58 publications

(81 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Besides, in the context of ROS, elevated TRPM2 expression gives rise to NLRP3 inflammasome activation. In the downstream, CD8 + T cell migration and effector function are both potentiated by IL‐1β/IL‐1R signaling 83 . Hence keratinocyte is decisive for recruiting autoreactive immunocytes to kill melanocytes, as elaborated in the last several emblematic studies.…”

Section: Oxidative Stressmentioning

confidence: 96%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

Self Cite

148

View full text Add to dashboard Cite

Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome‐wide associated studies have identified single‐nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte‐specific antigens exposure. Of note, the self‐responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type‐1‐skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8+ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well‐established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.

show abstract

Section: Oxidative Stressmentioning

confidence: 96%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

Self Cite

148

View full text Add to dashboard Cite

show abstract

“…In addition, our previous study illustrated that the expression of NLRP3 and downstream cytokine of IL-1β is upregulated in peripheral keratinocytes of vitiligo ( Li et al, 2019 ). The elevated IL-1β not only enhance the chemotaxis of CXCL16-CXCR6 and CXCL10-CXCR3 in keratinocytes, but also could reinforce the function of melanocyte-specific CD8 + T cells ( Li et al, 2019 ). To our knowledge, the existed off-table immunosuppress-targeting drugs is mainly focusing on the IFN-γ-JAK-chemokines signaling pathway, which exhibit the moderate effects in vitiligo therapy ( Frisoli and Harris, 2017 ).…”

Section: Discussionmentioning

confidence: 93%

“…Recently, we confirmed that oxidative stress promoted proinflammatory cytokine interleukin-1β (IL-1β) secretion from keratinocytes via nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) – caspase1 signaling pathway ( Li et al, 2019 ). NLRP3 is a member of nucleotide binding domain-like receptor (NLR) family, together with apoptosis-associated speck-like protein containing a CARD (ASC) and caspase1, forming NLRP3 inflammasome complex, which responds to microbes and danger signals and activates proinflammatory cytokines including IL-1β ( Jo et al, 2016 ; Chung et al, 2019 ).…”

Section: Introductionmentioning

confidence: 92%

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

Zhuang

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

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 pathway in keratinocyte still are not clear. In the present study, we initially found that TR could impede the secretion of IL-1β 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-1β. Additionally, TR could mitigate the secretion of inflammatory cytokines such as IL-6, IL-8, TNF-α, and IL-18 in keratinocytes under oxidative stress. In short, our data indicate that IL-1β 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-1β under oxidative stress.

show abstract

“…While under stress, it has been shown that keratinocytes increase the expression of transient receptor potential cation channel subfamily M member 2 (TRPM2), a redox‐sensitive cation channel, which in turn induces a rise in intracellular calcium intake (Kang et al., 2018). This is responsible for the activation of the NOD‐like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome (Li et al., 2020). These are central molecules in the regulation of innate immunity and NLRP3 potentiates IL‐1b and IL‐18 secretion.…”

Section: Non‐immunological Factors In Vitiligomentioning

confidence: 99%

An update on Vitiligo pathogenesis

Sénéschal

Boniface

D’Arino

et al. 2020

Pigment Cell Melanoma Res

View full text Add to dashboard Cite

Vitiligo, the most common depigmenting disorder of the skin, is undergoing a period of intense advances in both disease understanding and therapeutic possibilities leading the way to the beginning of a new era for the disorder. Its pathophysiology has gathered the attention of researchers for years, and many advances have been made in the clarification of the interaction between different factors that result in depigmented macule formation. The complex interplay between non‐immunological and immunological factors in vitiligo is key for the development of the disease, and the participation of cells other than melanocytes, such as keratinocytes, fibroblasts, natural killer cells, and innate lymphoid cells, has been shown. Recent advances have also brought to the understanding of the complex part played by a specific subtype of T cells: T‐resident memory cells. This review analyzes some of the most recent insights in vitiligo pathogenesis underlining the interactions between different cell types, which are the basis for the therapeutic approaches under development.

show abstract

Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo

Cited by 58 publications

References 61 publications

Mechanisms of melanocyte death in vitiligo

Mechanisms of melanocyte death in vitiligo

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

An update on Vitiligo pathogenesis

Contact Info

Product

Resources

About