Homocysteine induces melanocytes apoptosis via PERK–eIF2α–CHOP pathway in vitiligo

Chen, Jiaxi; Zhuang, Tongtian; Chen, Jianru; Tian, Yangzi; Yi, Xiuli; Ni, Qingrong; Zhang, Weigang; Song, P.; Jian, Zhe; Liu, Ling; Cui, Tongtong; Li, Kai; Gao, Tianwen; Li, Chunying; Li, Shuli

doi:10.1042/cs20200218

Cited by 18 publications

(16 citation statements)

References 50 publications

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“…In addition, tyrosine kinase c-Src has been implicated in a variety of cellular responses, including inflammation 45 . Hcy directly or indirectly participates in cell signal transduction by oxidative stress, which is induced by increasing the intracellular concentration of reactive oxygen species 46 . Moreover, c-Src phosphorylation at multiple sites, including Tyr416 and Tyr527, can directly regulate downstream target genes 47 .…”

Section: Resultsmentioning

confidence: 99%

FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE mice atherosclerosis

Zhang

Wang

et al. 2022

Laboratory Investigation

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Atherosclerosis is a chronic inflammatory vascular disease, and inflammation plays a critical role in its formation and progression. Elevated serum homocysteine (Hcy) is an independent risk factor for atherosclerosis. Previous studies have shown that fatty acid binding protein 4 (FABP4) plays an important role in macrophage inflammation and lipid metabolism in atherosclerosis induced by Hcy. However, the underlying molecular mechanism of FABP4 in Hcy-induced macrophage inflammation remains unknown. In this study, we found that FABP4 activated the Janus kinase 2/signal transducer and activator of transcription 2 (JAK2/STAT2) pathway in macrophage inflammation induced by Hcy. Of note, we further observed that ras-related protein Rap-1a (Rap1a) induced the Tyr416 phosphorylation and membrane translocation of non-receptor tyrosine kinase (c-Src) to activate the JAK2/STAT2 pathway. In addition, the suppressor of cytokine signaling 1 (SOCS1)—a transcriptional target of signal transducer and activator of transcription (STATs) inhibited the JAK2/STAT2 pathway and Rap1a expression via a negative feedback loop. In summary, these results demonstrated that FABP4 promotes c-Src phosphorylation and membrane translocation via Rap1a to activate the JAK2/STAT2 pathway, contributing to Hcy-accelerated macrophage inflammation in ApoE−/− mice.

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Section: Resultsmentioning

confidence: 99%

FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE mice atherosclerosis

Zhang

Wang

et al. 2022

Laboratory Investigation

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“…Oxidative stress is considered one of the most crucial initiators in vitiligo occurrence, 18 despite consensus on an exact etiology of vitiligo has not been established. Other factors like metabolism possibly engender melanocyte deaths, yet examples backing them up are sparse 19 . Oxidative stress is disturbed redox homeostasis characterized by the imbalance of prooxidants and antioxidants.…”

Section: Oxidative Stressmentioning

confidence: 99%

Mechanisms of melanocyte death in vitiligo

Chen

2020

Medicinal Research Reviews

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161

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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.

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“…We also found significant up-regulation of CHOP protein expression in the cold exposure group. CHOP is a C/EBP homologous protein, also known as proapoptotic factor, which is considered to be the late initiation of UPR-activated PERK-eIF-2α axis ( Chen et al, 2020 ). CHOP can directly regulate apoptosis factors, such as Bcl-2 and Bim, which subsequently make cells more prone to apoptosis ( Chitnis et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Cold Exposure Induces Intestinal Barrier Damage and Endoplasmic Reticulum Stress in the Colon via the SIRT1/Nrf2 Signaling Pathway

Guo

Chen

et al. 2022

Front. Physiol.

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Ambient air temperature is a key factor affecting human health. Long-term exposure to a cold environment can cause various diseases, while the impact on the intestine, the organ which has the largest contact area with the external environment, cannot be ignored. In this study, we investigated the effect of chronic cold exposure on the colon and its preliminary mechanism of action. Mice were exposed to 4°C for 3 hours a day for 10 days. We found that cold exposure damaged the morphology and structure of the colon, destroyed the tight junctions of the colonic epithelial tissue, and promoted inflammation of the colon. At the same time, cold exposure also activated the unfolded protein response (UPR) in the colon and promoted apoptosis in intestinal epithelial cells. Chronic cold exposure induced oxidative stress in vivo, but also significantly enhanced the response of the Nrf2 pathway that promotes an anti-oxidant effect. Furthermore, we demonstrated that chronic cold exposure promoted p65 acetylation to aggravate the inflammatory response by inhibiting SIRT1. Similar results were observed following SIRT1 knock-down by shRNA in Caco-2 cells treated with Thapsigargin (Tg). Knock-down of SIRT1 promoted nuclear localization of Nrf2, and increased the level of Nrf2 acetylation. Taken together, our study indicates that cold exposure may aggravate endoplasmic reticulum stress and damage epithelial tight junctions in the colon by inhibiting SIRT1, which promotes nuclear localization of Nrf2 and induces an anti-oxidant response to maintain intestinal homeostasis. These findings suggest that SIRT1 is a potential target for regulating intestinal health under cold exposure conditions.

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Homocysteine induces melanocytes apoptosis via PERK–eIF2α–CHOP pathway in vitiligo

Cited by 18 publications

References 50 publications

FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE mice atherosclerosis

FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE mice atherosclerosis

Mechanisms of melanocyte death in vitiligo

Cold Exposure Induces Intestinal Barrier Damage and Endoplasmic Reticulum Stress in the Colon via the SIRT1/Nrf2 Signaling Pathway

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