Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37

Conti, Pio; Lauritano, D; Caraffa, Alessandro; Gallenga, Carla Enrica; Kritas, S K; Ronconi, Gianpaolo; Martinotti, Stefano

doi:10.1016/j.ejphar.2020.173035

Cited by 52 publications

(36 citation statements)

References 47 publications

(62 reference statements)

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“…5C). Our results were consistent with previous studies [36][37][38] that p38 MAPK signaling was vital in activated microglia to release inflammatory cytokines, these findings also indirectly confirmed our hypothesis that activated microglial may lead to the apoptosis of photoreceptor by releasing inflammatory cytokines, which provides a plausible explanation about the mechanism between Aβ 1−42 induced microglia and photoreceptor apoptosis in AMD (Fig. 6).…”

Section: Discussionsupporting

confidence: 93%

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Gao

Shi

et al. 2020

Preprint

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Background Age-related macular degeneration (AMD) is mainly characterized by progressive deposits of drusen and photoreceptor apoptosis. Due to amyloid β (Aβ) is the main component of drusen, there is a great possibility that Aβ-induced activated microglia leads to inflammation, and plays a critical role in the pathogenesis of AMD. However, the relationship between activated microglia-mediated neuroinflammatory cytokines and photoreceptor apoptosis still remains unclarified. Results In this study, we demonstrated that subretinal injection of Aβ1−42 induced the microglia activation and increased inflammatory cytokines, gave rise to photoreceptor apoptosis in mice. Our results were verified in vitro by co-culture of Aβ1−42 activated primary microglia and photoreceptor cell line 661W, and we also performed that p38 MAPK signaling pathway was involved in Aβ1−42 induced microglia activation and inflammatory cytokines release. Conclusions Overall, our findings indicated that activated microglia-mediated neuroinflammatory cytokines contributed to photoreceptor apoptosis under the stimulation of Aβ1−42. Moreover, this study will provide a potential preventive and therapeutic approach for AMD treatment.

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Section: Discussionsupporting

confidence: 93%

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Gao

Shi

et al. 2020

Preprint

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“…Furthermore, with BIRB 796, the inhibitor of p38 MAPK phosphorylation, we found that the mRNA levels of in ammatory cytokines, including IL-1β, COX-2, TNF-a and iNOS, were decreased signi cantly under the treatment of BIRB 796 in microglia ( Figure 5C). Our results were consistent with previous studies [36][37][38] that p38 MAPK signaling was vital in activated microglia to release in ammatory cytokines, these ndings also indirectly con rmed our hypothesis that activated microglial may lead to the apoptosis of photoreceptor by releasing in ammatory cytokines, which provides a plausible explanation about the mechanism between Aβ 1-42 induced microglia and photoreceptor apoptosis in AMD ( Figure 6).…”

Section: Discussionsupporting

confidence: 93%

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Gao

Shi

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Age-related macular degeneration (AMD) is mainly characterized by progressive deposits of drusen and photoreceptor apoptosis. Due to amyloid β (Aβ) is the main component of drusen, there is a great possibility that Aβ-induced activated microglia leads to inflammation, and plays a critical role in the pathogenesis of AMD. However, the relationship between activated microglia-mediated neuroinflammatory cytokines and photoreceptor apoptosis still remains unclarified.Results: In this study, we demonstrated that subretinal injection of Aβ1-42 induced the microglia activation and increased inflammatory cytokines, gave rise to photoreceptor apoptosis in mice. Our results were verified in vitro by co-culture of Aβ1-42 activated primary microglia and photoreceptor cell line 661W, and we also performed that p38 MAPK signaling pathway was involved in Aβ1-42 induced microglia activation and inflammatory cytokines release.Conclusions: Overall, our findings indicated that activated microglia-mediated neuroinflammatory cytokines contributed to photoreceptor apoptosis under the stimulation of Aβ1-42. Moreover, this study will provide a potential preventive and therapeutic approach for AMD treatment.

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“…The epigenetic silence by promoter methylation and some transcription factors such as FOXO and v-myb directly regulate the Pdcd4 expression at the transcriptional level [18] [19]. SRSF3 modulates PDCD4 expression by inhibiting the alternative splicing and nuclear export of Pdcd4 mRNA at the post-transcriptional level [8,9]. Some non-coding RNAs, typically miR-21 and lncRNA MALAT1, bind and form sponging to target PDCD4 expression directly at the translational level [18] [19].…”

Section: Discussionmentioning

confidence: 99%

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

Chen

Lü

Duan

et al. 2021

Preprint

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Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It will be of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model on mice, we first reported an elevated expression of PDCD4 in both injured neurons and activated microglia of the inflamed mice brain. A similar change of PDCD4 expression was observed in the in vitro microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear transportation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPKs/NF-κB signaling activation to boost PDCD4 expression in microglia, and thus form a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic protein BAX, suggesting the pro-apoptotic activity of PDCD4 in the neuron. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes both the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4/MAPKs/NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury, and thus may become potential therapeutic targets for neuroinflammatory diseases.

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Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37

Cited by 52 publications

References 47 publications

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

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Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37

Cited by 52 publications

References 47 publications

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

PDCD4-MAPKs-NF-κB positive loop&nbsp;simultaneously&nbsp;promotes&nbsp;microglia activation and neuron apoptosis&nbsp;during&nbsp;neuroinflammation

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PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation