Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model

Kavanagh, Edel; Burguillos, Miguel Ángel; Carrillo-Jiménez, Alejandro; Oliva-Martín, Maria José; Santiago, Marti; Rodhe, Johanna; Joseph, Bertrand; Venero, José L.

doi:10.18632/aging.100805

Cited by 25 publications

(17 citation statements)

References 57 publications

(83 reference statements)

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“…4A) (P , 0.05). Interestingly, when the cells were treated with VX702 (50 mM), autophagy was significantly induced in microglia as determined by the ratio of LC3II/I, which is consistent with the results of the previous study (33) (Fig. 4B, C) (all P , 0.05).…”

Section: Knockdown Of P38 Suppresses the Secretion Of Proinflammatorysupporting

confidence: 92%

“…The procedures of double immunofluorescence staining were performed as previously described in Kavanagh et al (33). In brief, free-floating 30-mm sections of the midbrain from each group were incubated with rabbit-derived anti-Iba-1 (019-19741, 1:500; Wako Pure Chemicals, Tokyo, Japan), rabbit anti-p-p38 (8632, 1:50; Cell Signaling Technology), rabbit anti-p62 (GB11005, 1:100; Servicebio, Wuhan, China) at 4°C overnight followed by Cy3 conjugated goat anti-rabbit IgG (GB21303, 1:300; Servicebio), or a goat anti-mouse IgG conjugated with Alexa Fluor 488 (GB25301, 1:400; Servicebio) for 1 h at room temperature (22 6 2°C).…”

Section: Double Immunofluorescence Staining and Confocal Laser Scannimentioning

confidence: 99%

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MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Yao

Zhu

et al. 2019

FASEB j.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain‐specific microRNA‐124 (miR‐124) is significantly down‐regulated in the 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR‐124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho‐p38 mitogen‐activated protein kinases (p‐p38) showed a significant increase in LPS‐treated immortalized murine microglial cell line BV2 cells in an MPTP‐induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p‐p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR‐124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH‐SY5Y (SH‐SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR‐124 could suppress p62 and p‐p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP‐treated mice. Taken together, our data suggest that miR‐124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR‐124 could be a potential therapeutic target for regulating the inflammatory response in PD.—Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease. FASEB J. 33,8648–8665 (2019). http://www.fasebj.org

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Section: Knockdown Of P38 Suppresses the Secretion Of Proinflammatorysupporting

confidence: 92%

Section: Double Immunofluorescence Staining and Confocal Laser Scannimentioning

confidence: 99%

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Yao

Zhu

et al. 2019

FASEB j.

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“…For monocyte isolation, 6-8 week-old mice were sacrificed by cervical dislocation and the bone marrow was harvested by standard techniques. Monocytes were then purified by negative selection using the BM Monocyte Isolation Kit (Miltenyi Biotec S.L., Bergisch Gladbach, Germany) [30], following manufacturer's instructions, and cultured in RPMI-1640 supplemented with 10% FBS. To induce monocyte activation, 2×10 5 primary human and murine monocytes were plated in flat-bottom 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

Caspase-8 inhibition represses initial human monocyte activation in septic shock model

et al. 2016

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In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1β and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source.

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“…Caspase-8 is a cysteine protease that is mainly expressed in bone and cartilage tissues and cells. It has a death effect domain that can bind with the Fas-associated protein with death domain (FADD), enabling its participation in cell apoptosis (Kavanagh et al, 2015;Polanski et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Correlation between TRAIL and caspase-8 expression and their relationship with cell proliferation and apoptosis in human osteosarcoma

Xu¹,

Shang²,

Zhuang³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Osteosarcoma is a common malignant bone tumor that mainly affects children and adolescents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily. Caspase-8 appears in the upstream of apoptosis signaling pathway among caspases. We investigated TRAIL and caspase-8 levels in osteosarcoma patients to determine their correlation with cell proliferation and apoptosis. Osteosarcoma and osteochondroma patients receiving surgery in our hospital were selected. TRAIL and caspase-8 expression levels in tissue were determined by immunohistochemistry, and protein levels in cells were evaluated by western blotting. Human osteosarcoma cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The osteosarcoma and osteochondroma cell cycles and apoptosis were investigated by flow cytometry. Correlation analysis was applied to TRAIL and caspase-8 levels during cell apoptosis. Positive TRAIL and caspase-8 expression rates in osteosarcoma tissue were significantly lower than in the controls (P < 0.05). TRAIL (0.114 ± 0.002) and caspase-8 (0.352 ± 0.124) levels in experimental cells were obviously lower than in the controls (P < 0.05). Osteosarcoma cells in the experimental group demonstrated higher proliferation and lower apoptosis at 24, 48, and 72 h (P < 0.05). The experimental cell number increased in the G1 stage and decreased in the S stage (P < 0.05). TRAIL and caspase-8 proteins showed positive correlation with apoptosis in osteosarcoma (P < 0.05). Human osteosarcoma presented reduced TRAIL and caspase-8 levels with enhanced cell proliferation and reduced apoptosis. TRAIL and caspase-8 expression levels were positively correlated with apoptosis in osteosarcoma.

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Deletion of caspase-8 in mouse myeloid cells blocks microglia pro-inflammatory activation and confers protection in MPTP neurodegeneration model

Cited by 25 publications

References 57 publications

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Caspase-8 inhibition represses initial human monocyte activation in septic shock model

Correlation between TRAIL and caspase-8 expression and their relationship with cell proliferation and apoptosis in human osteosarcoma

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