Protective Role of Autophagy in Nlrp3 Inflammasome Activation and Medial Thickening of Mouse Coronary Arteries

Yuan, Xinxu; Bhat, Owais M.; Meng, Nan; Lohner, Hannah; Li, Pin‐Lan

doi:10.1016/j.ajpath.2018.08.014

Cited by 28 publications

(24 citation statements)

References 57 publications

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“…Furthermore, it has been reported that metformin activates autophagy via SIRT1 53 , and that SIRT1 could modulate the inhibition of NLRP3 inflammasome activation 54,55 . Considering the evidence that AMPK, SIRT1 and autophagy are coordinately regulated 56 , and that autophagy induction negatively regulates NLRP3 inflammasome activation [57][58][59] , there is a possibility that autophagy through AMPK and SIRT1 activation may be involved in the lowered caspase-1 protein expression induced by metformin, contributing to the inhibition of NLRP3 activation and IL-1β secretion (mature IL-1β); however, to demonstrate this, further studies are required. Recently, the IL-1β-IL-1R signalling pathway controlled by NLPR3 inflammasome has been reported to play a critical role in the pathogenesis of psoriasis in humans and induced by IMQ in mice 60 .…”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Tsuji

Hashimoto-Hachiya

et al. 2020

Cell Death Discov.

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Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1β secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-α and IL-17A. This stimulation induced the upregulation of pro-IL-1β mRNA and protein levels, and subsequently mature IL-1β secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-α and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogated the downregulation of caspase-1 induced by metformin treatment, indicating that AMPK and SIRT1 are essential for the inhibitory effect on NLRP3 inflammasome in NHEKs. As IL-1β stimulation induced upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels in NHEKs, we examined whether metformin treatment affects such gene expression. Metformin treatment inhibited upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-α and IL-17A stimulation. Finally, we examined whether metformin administration affected psoriasis development in an imiquimod-induced mouse psoriasis model. Oral metformin treatment significantly decreased ear thickness, epidermal hyperplasia and inflammatory cell infiltration. A cytokine profile in the epidermis under metformin treatment showed that IL-1β, Cxcl1, Cxcl2, S100a7, S100a8 and S100A9 mRNA levels were downregulated compared with control levels. These results indicate that metformin administration prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients.

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Section: Discussionmentioning

confidence: 99%

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Tsuji

Hashimoto-Hachiya

et al. 2020

Cell Death Discov.

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“…Finally, the slides were cleared and mounted with DPX. Image-Pro Plus 6.0 software (Rockvile, MD, USA) was used to calculate the area percentage of the positive staining [71].…”

Section: Immunohistochemical Analysesmentioning

confidence: 99%

“…The rate of co-localization of Lamp-1 with RAB7, ALG-2, VPS16 in the aortic medial SMCs was expressed by Pearson's Correlation Coefficient (PCC) using Image-Pro Plus 6.0 software (Media Cybernetics, Bethesda, MD, USA). PCC is determined by correlation coefficient, r (r = −1 to 0), as mentioned previously [71,72].…”

Section: Immunofluorescent Stainingmentioning

confidence: 99%

“…Milk (5%) was used for blocking the membrane, followed by incubation with respective primary antibodies rabbit polyclonal to SM22-α (1:10,000, abcam, Cambridge, MA, USA), rabbit polyclonal to RUNX2 (1:1000, abcam, USA) and rabbit anti-β-actin (1:10,000, Santa Cruz Biotechnology, Dallas, TX, USA) overnight at 4 • C. Next day incubated with donkey anti-rabbit-HRP IgG (1:5000, Santa Cruz Biotechnology, Dallas, TX, USA) for 1 h at room temperature. Finally, bands were detected by chemiluminescence technique using LI-COR Odyssey Fc and the band intensity of target proteins was normalized to β-actin and calculated with Image J software version 1.44 p (NIH, Bethesda, MD, USA) [71].…”

Section: Western Blot Analysismentioning

confidence: 99%

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Abnormal Lysosomal Positioning and Small Extracellular Vesicle Secretion in Arterial Stiffening and Calcification of Mice Lacking Mucolipin 1 Gene

Bhat

Yuan

Camus

et al. 2020

IJMS

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Recent studies have shown that arterial medial calcification is mediated by abnormal release of exosomes/small extracellular vesicles from vascular smooth muscle cells (VSMCs) and that small extracellular vesicle (sEV) secretion from cells is associated with lysosome activity. The present study was designed to investigate whether lysosomal expression of mucolipin-1, a product of the mouse Mcoln1 gene, contributes to lysosomal positioning and sEV secretion, thereby leading to arterial medial calcification (AMC) and stiffening. In Mcoln1 −/− mice, we found that a high dose of vitamin D (Vit D; 500,000 IU/kg/day) resulted in increased AMC compared to their wild-type littermates, which was accompanied by significant downregulation of SM22-α and upregulation of RUNX2 and osteopontin in the arterial media, indicating a phenotypic switch to osteogenic. It was also shown that significantly decreased co-localization of lysosome marker (Lamp-1) with lysosome coupling marker (Rab 7 and ALG-2) in the aortic wall of Mcoln1 −/− mice as compared to their wild-type littermates. Besides, Mcoln1 −/− mice showed significant increase in the expression of exosome/ sEV markers, CD63, and annexin-II (AnX2) in the arterial medial wall, accompanied by significantly reduced co-localization of lysosome marker (Lamp-1) with multivesicular body (MVB) marker (VPS16), suggesting a reduction of the lysosome-MVB interactions. In the plasma of Mcoln1 −/− mice, the number of sEVs significantly increased as compared to the wild-type littermates. Functionally, pulse wave velocity (PWV), an arterial stiffening indicator, was found significantly increased in Mcoln1 −/− mice, and Vit D treatment further enhanced such stiffening. All these data indicate that the Mcoln1 gene deletion in mice leads to abnormal lysosome positioning and increased sEV secretion, which may contribute to the arterial stiffness during the development of AMC.

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“…In the current study, we show that the levels of p62/sqtsm1 and LC3II, as well as the levels of NLRP3, caspase1, and IL-1β, increased after treatment with bafA1, thereby confirming that the activation of NLRP3 inflammatory corpuscles may be related to the intracellular accumulation of p62. Additionally, in vivo experiments have shown that inhibition of lysosomal function enhances the formation and activation of NLRP3 inflammatory bodies [35]. Alternatively, pyroptosis has also been reported to have a regulatory role in autophagy.…”

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confidence: 99%

MicroRNA-103 Protects Coronary Artery Endothelial Cells against H₂O₂-Induced Oxidative Stress via BNIP3-Mediated End-Stage Autophagy and Antipyroptosis Pathways

Wang

Song

et al. 2020

Oxidative Medicine and Cellular Longevity

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Endothelial cell damage caused by oxidative stress is widely considered to be a triggering event in atherosclerosis (AS). However, the specific effect elicited by autophagy in endothelial cells undergoing oxidative stress remains controversial, especially during endstage autophagy. The inhibition of end-stage autophagy has been reported to increase cell pyroptosis and contribute to endothelial damage. Several studies have shown that microRNA-103 is involved in end-stage autophagy; however, its specific mechanism of action is not yet characterized. In this study, we addressed the regulatory role of miR-103 in autophagy during oxidative stress of endothelial cells. Hydrogen peroxide (H 2 O 2 ) treatment was used as an in vitro model of oxidative stress. MTS and ROS levels were measured to evaluate cell activity. qRT-PCR was used to detect the expression of miR-103. Autophagy was examined using western blot, immunofluorescence staining, and electron microscopy, while western blot analysis detected pyroptosis-related proteins. Results show that miR-103 expression decreased under oxidative stress. Further, miR-103 repressed transcription of Bcl-2/adenovirus E1B 19 kDa interacting protein (BNIP3). The oxidative stress caused by H 2 O 2 caused cell damage from 2 hours (P < 0:05) and increased the level of intracellular reactive oxygen species (P < 0:05); at the same time, the damage could be further aggravated by the stimulation of bafA1 (P < 0:05). Under the stimulation of H 2 O 2 , the expression of miR-103 decreased (P < 0:05). However, high expression of miR-103 could reduce the accumulation of LC3II and P62 (P < 0:05) by inhibiting the downstream target gene Bcl-2/adenovirus E1B 19 kDa interacting protein (BNIP3), thus reducing the occurrence of cell pyroptosis (P < 0:05). This process could be blocked by end-stage autophagy inhibitor bafA1 (P < 0:05), which further indicated that miR-103 affected cell injury by autophagy. On the contrary, the low expression of miR-103 promoted the accumulation of autophagy protein and increased the occurrence of pyroptosis (P < 0:05). In conclusion, inhibition of miR-103 restrained end-stage of autophagy by regulating BNIP3, thus changing the occurrence of cell pyroptosis.

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Protective Role of Autophagy in Nlrp3 Inflammasome Activation and Medial Thickening of Mouse Coronary Arteries

Cited by 28 publications

References 57 publications

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Abnormal Lysosomal Positioning and Small Extracellular Vesicle Secretion in Arterial Stiffening and Calcification of Mice Lacking Mucolipin 1 Gene

MicroRNA-103 Protects Coronary Artery Endothelial Cells against H₂O₂-Induced Oxidative Stress via BNIP3-Mediated End-Stage Autophagy and Antipyroptosis Pathways

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Protective Role of Autophagy in Nlrp3 Inflammasome Activation and Medial Thickening of Mouse Coronary Arteries

Cited by 28 publications

References 57 publications

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Abnormal Lysosomal Positioning and Small Extracellular Vesicle Secretion in Arterial Stiffening and Calcification of Mice Lacking Mucolipin 1 Gene

MicroRNA-103 Protects Coronary Artery Endothelial Cells against H2O2-Induced Oxidative Stress via BNIP3-Mediated End-Stage Autophagy and Antipyroptosis Pathways

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MicroRNA-103 Protects Coronary Artery Endothelial Cells against H₂O₂-Induced Oxidative Stress via BNIP3-Mediated End-Stage Autophagy and Antipyroptosis Pathways