Rapamycin regulates macrophage activation by inhibiting NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62-dependent manners

Ko, Jung Hwa; Yoon, Sun Woo; Lee, Hyun Ju; Oh, Joo Youn

doi:10.18632/oncotarget.17256

Cited by 147 publications

(113 citation statements)

References 69 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…It accumulates when autophagy is deficient. Previous studies demonstrate that rapamycin treatment inceased p62 levels in different cell lines and may have enhanced effects on autophagy . In agreement with these previous reports our results demonstrate an increase in p62 with rapamycin treatment and this increase in p62 levels dropped significantly with Burkholderia infection in vitro compared to only Burkholderia infection.…”

Section: Discussionsupporting

confidence: 93%

An increase in intracellular p62/NBR1 and persistence of Burkholderia mallei and B. pseudomallei in infected mice linked to autophagy deficiency

Saikh

Dankmeyer

Zeng

et al. 2018

Immunity Inflam & Disease

View full text Add to dashboard Cite

Introduction Burkholderia mallei ( B. mallei ) and Burkholderia pseudomallei ( B. pseudomallei ), causative agents of glanders and melioidosis, respectively, are invasive intracellular pathogens that actively multiply in phagocytic and non‐phagocytic cells. Activation of cell‐autonomous autophagy mechanism eliminate intracellular pathogens in which p62 a cytosolic cargo protein is selectively degraded, and an accumulation of this marker occurs if autophagy is deficient. Recurrent, relapsed and reinfection of B. pseudomallei in melioidosis patients in endemic area indicative of lack of complete of clearance and persistence of the pathogen. Reasoning that abundance in the levels of p62 may provide an indication of the intracellular infection, we sought to examine whether increase in intracellular p62 and bacterial burden with Burkholderia infection are linked to autophagy deficiency. Methods In this study, we investigated cell culture and mouse models of disease to identify an association between autophagy biomarkers (p62/NBR1) accumulation and intracellular persistence of B. mallei and B. pseudomallei . Results We demonstrate, that elevated levels of intracellular p62/NBR1 correlated with bacterial persistence, while pre‐treatment with a pharmacological inducer of autophagy, rapamycin, reduced both intracellular p62, and bacterial survival. Our results showed an elevated p62 levels (2‐5 fold) in spleen and liver cells of Burkholderia ‐infected BALB/c mice, as well as in spleen cells of Burkholderia ‐infected C57BL/6 mice, suggesting that an increase in p62/NBR1 was due to an autophagy deficiency. Similar to p62, cytosolic LC3‐I levels were also elevated, while the characteristic conversion to the autophagosome‐associated membrane bound form LC3‐II was low in spleens of the infected mice further supporting the conclusion that autophagy was deficient. Conclusion Taken together, our results suggest that an increase in intracellular p62/NBR1 may be a potential host cell biomarker of B. mallei or B. pseudomallei infections, and identifying autophagy manipulation may potentially aid to therapeutic approach for complete clearance of the pathogen.

show abstract

Section: Discussionsupporting

confidence: 93%

An increase in intracellular p62/NBR1 and persistence of Burkholderia mallei and B. pseudomallei in infected mice linked to autophagy deficiency

Saikh

Dankmeyer

Zeng

et al. 2018

Immunity Inflam & Disease

View full text Add to dashboard Cite

show abstract

“…There is increasing evidence that autophagy has a regulatory function in inflammation as well as having an antiinflammatory effect [31,32]. However some reports found that autophagy might …”

Section: Exos From Mir-30d-5p-overexpressing Adscs Are More Effectivementioning

confidence: 99%

Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization

Jiang

Wang

Jin

et al. 2018

Cell Physiol Biochem

253

191

View full text Add to dashboard Cite

Background/Aims: Recent studies have indicated that exosomes secreted from adipose-derived stem cells (ADSCs) have important effects in the treatment of ischemic injury. However, the treatment mechanism is unclear. This study aimed to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-30d-5p have a protective effect on acute ischemic stroke (AIS). Methods: In the current study, inflammatory factors and miR-30d-5p expression were assessed in 70 subjects with AIS and 35 healthy controls. Exosomes were characterized by transmission electron microscopy and further examined using nanoparticle tracking analyses. A rat model of AIS and an in vitro model of oxygen- and glucose-deprived (OGD) primary microglia were established to study the protective mechanism of exosomes from miR-30d-5p-overexpressing ADSCs in ischemia-induced nerve injury. Results: The results showed that following AIS, the expression of inflammatory cytokines increased, while the anti-inflammatory cytokines IL-4, IL-10, and miR-30d-5p decreased both in patients and in animal models. Moreover, in vitro studies demonstrated that suppression of autophagy significantly reduced the OGD-induced inflammatory response. In addition, exosome treatment was more effective in suppressing the inflammatory response by reversing OGD-induced and autophagy-mediated microglial polarization to M1. Furthermore, in vivo studies showed that exosomes derived from ADSCs significantly decreased the cerebral injury area of infarction by suppressing autophagy and promoting M2 microglia/macrophage polarization. Conclusions: Our results suggest that miR-30d-5p-enhanced ADSC-derived exosomes prevent cerebral injury by inhibiting autophagy-mediated microglial polarization to M1.

show abstract

“…In addition, recent evidence suggests that NLRP3 is a convergent point of antiaging interventions. NLRP3 inflammasome is inhibited by rapamycin, metformin, or resveratrol through regulation of mTOR, AMPK, and Sirt1 [130,131]. Interestingly, nutrients status is shown to modulate the NLRP3 inflammasome in human and mouse.…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

Autophagy and cardiac aging

Miyamoto

2019

Cell Death Differ

View full text Add to dashboard Cite

Cardiovascular disease (CVD) is the leading cause of death and the prevalence of CVD dramatically increases with age. Cardiac aging is associated with hypertrophy, fibrosis, inflammation, and decreased contractility. Autophagy, a bulk degradation/recycling system, is essential to maintain cellular homeostasis. Cardiac autophagy is decreased with age, and misfolded proteins and dysfunctional mitochondria are accumulated in the aging heart. Inhibition of autophagy leads to exacerbated cardiac aging, while stimulation of autophagy improves cardiac function and also increases lifespan in many organisms. Thus autophagy represents a potential therapeutic target for aging-related cardiac dysfunction. This review discusses recent progress in our understanding of the role and regulation of autophagy in the aging heart. Facts• Cardiac aging is associated with hypertrophy, fibrosis, inflammation, and contractile dysfunction.

show abstract

Rapamycin regulates macrophage activation by inhibiting NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62-dependent manners

Cited by 147 publications

References 69 publications

An increase in intracellular p62/NBR1 and persistence of Burkholderia mallei and B. pseudomallei in infected mice linked to autophagy deficiency

An increase in intracellular p62/NBR1 and persistence of Burkholderia mallei and B. pseudomallei in infected mice linked to autophagy deficiency

Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization

Autophagy and cardiac aging

Contact Info

Product

Resources

About