Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation

Deo, Pankaj; Chow, Seong Hoong; Han, Mei‐Ling; Speir, Mary; Huang, Cheng; Schittenhelm, Ralf B.; Dhital, Subhash; Emery, Jack; Li, Jian; Kile, Benjamin T.; Vince, James E.; Lawlor, Kate E.; Naderer, Thomas

doi:10.1038/s41564-020-0773-2

Cited by 132 publications

(131 citation statements)

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“…The inflammation and apoptosis were major characteristics after sepsis and their occurrence was related to mitochondrial dysfunction ( Deo et al, 2020 ). Therefore, inflammation and apoptosis in cardiac muscle and vascular smooth muscle were observed.…”

Section: Resultsmentioning

confidence: 99%

Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

Zhu

Kuang

et al. 2021

Front. Pharmacol.

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Sepsis-associated organ dysfunction plays a critical role in its high mortality, mainly in connection with mitochondrial dysfunction. Whether the inhibition of mitochondrial fission is beneficial to sepsis-related organ dysfunction and underlying mechanisms are unknown. Cecal ligation and puncture induced sepsis in rats and dynamic related protein 1 knockout mice, lipopolysaccharide-treated vascular smooth muscle cells and cardiomyocytes, were used to explore the effects of inhibition of mitochondrial fission and specific mechanisms. Our study showed that mitochondrial fission inhibitor Mdivi-1 could antagonize sepsis-induced organ dysfunction including heart, vascular smooth muscle, liver, kidney, and intestinal functions, and prolonged animal survival. The further study showed that mitochondrial functions such as mitochondrial membrane potential, adenosine-triphosphate contents, reactive oxygen species, superoxide dismutase and malonaldehyde were recovered after Mdivi-1 administration via improving mitochondrial morphology. And sepsis-induced inflammation and apoptosis in heart and vascular smooth muscle were alleviated through inhibition of mitochondrial fission and mitochondrial function improvement. The parameter trends in lipopolysaccharide-stimulated cardiomyocytes and vascular smooth muscle cells were similar in vivo. Dynamic related protein 1 knockout preserved sepsis-induced organ dysfunction, and the animal survival was prolonged. Taken together, this finding provides a novel effective candidate therapy for severe sepsis/septic shock and other critical clinical diseases.

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Section: Resultsmentioning

confidence: 99%

Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

Zhu

Kuang

et al. 2021

Front. Pharmacol.

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“…Thus, continuous mitochondrial injury caused by these molecules would initiate inappropriate or sustained inflammasome signaling, named mitochondrial activation of the inflammasome [ 28 ]. In detail, p-MAP4 made the outer membrane vesicles to open, leading to mitochondrial apoptosis, mitochondrial DNA release, and potassium ion efflux [ 22 , 29 , 30 ]. Therefore, mitochondrial impairment induced by the phosphorylation of MAP4 should be regarded as the core mechanism of the p-MAP4-induced activation of the NLRP3 inflammasome in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis

Feng

Zhang

et al. 2021

Cell Death Discov.

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Phosphorylation of MAP4 (p-MAP4) causes cardiac remodeling, with the cardiac microvascular endothelium being considered a vital mediator of this process. In the current study, we investigated the mechanism underlying p-MAP4 influences on cardiac microvascular density. We firstly confirmed elevated MAP4 phosphorylation in the myocardium of MAP4 knock-in (KI) mice. When compared with the corresponding control group, we detected the decreased expression of CD31, CD34, VEGFA, VEGFR2, ANG2, and TIE2 in the myocardium of MAP4 KI mice, accompanied by a reduced plasma concentration of VEGF. Moreover, we observed apoptosis and mitochondrial disruption in the cardiac microvascular endothelium of MAP4 KI animals. Consistently, we noted a decreased cardiac microvascular density, measured by CD31 and lectin staining, in MAP4 KI mice. To explore the underlying mechanism, we targeted the NLRP3-related pyroptosis and found increased expression of the corresponding proteins, including NLRP3, ASC, mature IL-1β, IL-18, and GSDMD-N in the myocardium of MAP4 KI mice. Furthermore, we utilized a MAP4 (Glu) adenovirus to mimic cellular p-MAP4. After incubating HUVECs with MAP4 (Glu) adenovirus, the angiogenic ability was inhibited, and NLRP3-related pyroptosis were significantly activated. Moreover, both cytotoxicity and PI signal were upregulated by the MAP4 (Glu) adenovirus. Finally, NLRP3 inflammasome blockage alleviated the inhibited angiogenic ability induced by MAP4 (Glu) adenovirus. These results demonstrated that p-MAP4 reduced cardiac microvascular density by activating NLRP3-related pyroptosis in both young and aged mice. We thus managed to provide clues explaining MAP4 phosphorylation-induced cardiac remodeling and enriched current knowledge regarding the role of MAP4.

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“…Furthermore, a second study also showed the contribution of capsase-11 to OMV-mediated pathology, as mice deficient in caspase-11 treated with E. coli OMVs had significantly reduced IL-1β and IL-18 cytokine responses, which suggests an important role for caspases and inflammasome activation in response to OMVs [51]. Other Gram-negative pathogens including N. gonorrhoeae, uropathogenic E. coli and P. aeruginosa also produce OMVs that induce mitochondrial apoptosis and NLRP3 activation in murine BMDMs [65]. Collectively, these studies highlight the ability of OMVs produced by a range of Gram-negative pathogens to activate caspase-11 and NLRP3 inflammasome activation in the host, to modulate inflammation and promote pathogenesis.…”

Section: Inflammasome Activation By Bmvsmentioning

confidence: 92%

Detection of Bacterial Membrane Vesicles by NOD-Like Receptors

Johnston

Heras

Kufer

et al. 2021

IJMS

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Bacterial membrane vesicles (BMVs) are nanoparticles produced by both Gram-negative and Gram-positive bacteria that can function to modulate immunity in the host. Both outer membrane vesicles (OMVs) and membrane vesicles (MVs), which are released by Gram-negative and Gram-positive bacteria, respectively, contain cargo derived from their parent bacterium, including immune stimulating molecules such as proteins, lipids and nucleic acids. Of these, peptidoglycan (PG) and lipopolysaccharide (LPS) are able to activate host innate immune pattern recognition receptors (PRRs), known as NOD-like receptors (NLRs), such as nucleotide-binding oligomerisation domain-containing protein (NOD) 1, NOD2 and NLRP3. NLR activation is a key driver of inflammation in the host, and BMVs derived from both pathogenic and commensal bacteria have been shown to package PG and LPS in order to modulate the host immune response using NLR-dependent mechanisms. Here, we discuss the packaging of immunostimulatory cargo within OMVs and MVs, their detection by NLRs and the cytokines produced by host cells in response to their detection. Additionally, commensal derived BMVs are thought to shape immunity and contribute to homeostasis in the gut, therefore we also highlight the interactions of commensal derived BMVs with NLRs and their roles in limiting inflammatory diseases.

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Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation

Cited by 132 publications

References 50 publications

Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

Microtubule associated protein 4 (MAP4) phosphorylation reduces cardiac microvascular density through NLRP3-related pyroptosis

Detection of Bacterial Membrane Vesicles by NOD-Like Receptors

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