Sirt6-induced autophagy restricted TREM-1-mediated pyroptosis in ox-LDL-treated endothelial cells: relevance to prognostication of patients with acute myocardial infarction

Ye, Zi; Yao, Yihong; Jia, Bing; Liu, Yan; Tong, Jing; Guan, Chunyu; Fan, Ping; Lin, Hao; Tang, Jiayou; Hou, Han-Jin; Fei, Chen; Liu, Xuebo

doi:10.1038/s41420-019-0168-4

Cited by 38 publications

(33 citation statements)

References 48 publications

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“…Conversely, TREM1 inhibition alleviates ER stress and rescues the autophagy pathway, which ameliorates gut dysbiosis and reduces colitis severity. In addition, oxidatively modified low-density lipoprotein (ox-LDL)-treated endothelial cells (ECs) exhibit increased TREM-1-mediated pyroptosis and decreased Sirt6-induced autophagy [103]. Conversely, blockage of Sirt6-induced autophagy augments TREM-1-mediated pyroptosis, whereas Sirt6 overexpression attenuates ECs inflammation and pyroptosis following ox-LDL treatment.…”

Section: Autophagy As An Emerging Pathway Related To Trems Pathophmentioning

confidence: 99%

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

Natale

Biagioni

Busceti

et al. 2019

Cells

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Alterations in Triggering Receptors Expressed on Myeloid cells (TREM-1/2) are bound to a variety of infectious, sterile inflammatory, and degenerative conditions, ranging from inflammatory bowel disease (IBD) to neurodegenerative disorders. TREMs are emerging as key players in pivotal mechanisms often concurring in IBD and neurodegeneration, namely microbiota dysbiosis, leaky gut, and inflammation. In conditions of dysbiosis, compounds released by intestinal bacteria activate TREMs on macrophages, leading to an exuberant pro-inflammatory reaction up to damage in the gut barrier. In turn, TREM-positive activated macrophages along with inflammatory mediators may reach the brain through the blood, glymphatic system, circumventricular organs, or the vagus nerve via the microbiota-gut-brain axis. This leads to a systemic inflammatory response which, in turn, impairs the blood-brain barrier, while promoting further TREM-dependent neuroinflammation and, ultimately, neural injury. Nonetheless, controversial results still exist on the role of TREM-2 compared with TREM-1, depending on disease specificity, stage, and degree of inflammation. Therefore, the present review aimed to provide an update on the role of TREMs in the pathophysiology of IBD and neurodegeneration. The evidence here discussed the highlights of the potential role of TREMs, especially TREM-1, in bridging inflammatory processes in intestinal and neurodegenerative disorders.

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Section: Autophagy As An Emerging Pathway Related To Trems Pathophmentioning

confidence: 99%

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

Natale

Biagioni

Busceti

et al. 2019

Cells

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“…Sirtuins (SIRT1-SIRT7) are evolutionary conserved nicotinamide adenine dinucleotide (NAD + )-dependent class III histone deacetylases which have attracted much attention for their roles in cardiovascular and metabolic diseases. 24 As an important member of sirtuin family, SIRT6 is mainly located in the nucleus and its activation exerts protective effects against myocardial infarction, 25 cardiac hypertrophy, 26 and heart failure. 27 Besides, numerous studies have reported that sirtuins mediated the pleiotropic actions of melatonin in various disease models.…”

Section: Introductionmentioning

confidence: 99%

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

Dong

Xue

et al. 2020

Journal of Pineal Research

155

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Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high‐fat diet‐streptozotocin‐induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK‐PGC‐1α‐AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia‐reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re‐activating SIRT6 and AMPK‐PGC‐1α‐AKT signaling. After the induction of diabetes, adeno‐associated virus carrying SIRT6‐specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin‐induced AMPK‐PGC‐1α‐AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long‐term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor‐mediated SIRT6‐AMPK‐PGC‐1α‐AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia‐reperfusion injury in diabetic patients.

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“…A growing body of evidence indicates that autophagic flux becomes defective in macrophages of advanced atherosclerotic plaques, and that treatment with an autophagy inducer can be exploited as a potential strategy to prevent plaque formation and destabilization ( 8 ). In endothelial cells cultured in vitro oxLDL-induced pyroptosis is restricted by autophagy ( 29 ). Consequently, we speculated whether, in our foam macrophages, pyroptosis can be counterbalanced by induction of autophagy.…”

Section: Resultsmentioning

confidence: 99%

Phenotype and Response to PAMPs of Human Monocyte-Derived Foam Cells Obtained by Long-Term Culture in the Presence of oxLDLs

et al. 2020

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Cholesterol-laden, foam macrophages constitute the most characteristic component of human atherosclerotic plaques. Persistent uptake of oxLDLs results in accumulation of lipid bodies inside the cells and determines their phenotype and subsequent functions. In this work, we describe the phenotype of human monocyte-derived foam cells obtained by differentiation in the constant presence of oxLDLs for 30 days (prolonged-hMDFCs). Although neither the total cellular nor the cell surface expression of Toll-like receptors (TLR) was regulated by oxLDLs, the prolonged-hMDFCs changed dramatically their responsiveness to TLR ligands and inactivated bacteria. Using multiplex technology, we observed an acute decline in cytokine and chemokine production after surface and endosomal TLR stimulation with the exception of TLR2/6 triggering with agonists Pam2CSK4 and MALP-2. We also noted significant reduction of some surface receptors which can have accessory function in recognition of particulate antigens (CD47, CD81, and CD11b). In contrast, the prolonged-hMDFCs responded to inflammasome activation by LPS/nigericin with extensive, necrotic type cell death, which was partially independent of caspase-1. This pyroptosis-like cell death was aggravated by necrostatin-1 and rapamycin. These findings identify a potential contribution of mature foam cells to inflammatory status by increasing the immunogenic cell death burden. The observed cross-talk between foam cell death pathways may lead to recognition of a potential new marker for atherosclerosis disease severity. Overall, our study demonstrates that, in contrast to other cellular models of foam cells, the prolonged-hMDFCs acquire a functional phenotype which may help understanding the role of foam cells in the pathogenesis of atherosclerosis.

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Sirt6-induced autophagy restricted TREM-1-mediated pyroptosis in ox-LDL-treated endothelial cells: relevance to prognostication of patients with acute myocardial infarction

Cited by 38 publications

References 48 publications

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

Phenotype and Response to PAMPs of Human Monocyte-Derived Foam Cells Obtained by Long-Term Culture in the Presence of oxLDLs

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