Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation

Li, Qian; Dai, Zhenguo; Cao, Yuze; Wang, Lihua

doi:10.1016/j.bbrc.2019.03.202

Cited by 63 publications

(47 citation statements)

References 25 publications

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“…Furthermore, as a key transcription factor, activated NF-κB induces the transcription of many pro-inflammatory genes (COX-2, TNF-α, IL-1β, IL-6, iNOS, and IL-12) and plays a key role in M1 polarization (28)(29)(30). The activity of NF-κB is rapidly induced in response to pro-inflammatory stimuli and results in the proteasomal degradation of IκBs and the release of NF-κB p65/p50 heterodimers from the NF-κB/IκBs complex.…”

Section: Discussionmentioning

confidence: 99%

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Shi

Zhang

et al. 2020

Front. Neurol.

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Intracerebral hemorrhage (ICH) is a fatal subtype of stroke, and effective interventions to improve the functional outcomes are still lacking. Suppressor of cytokine signaling 3 (SOCS3) plays critical roles in the inflammatory response by negatively regulating cytokine-Jak–Stat signaling. However, the role of SOCS3 in the regulation of macrophage polarization is highly controversial and the fine regulation exerted by SOCS3 needs further understanding. In this study, rat ICH models were established by infusion of collagenase into the caudate nucleus. To decrease SOCS3 expression into microglia/macrophages in the hemorrhagic lesion area, we injected lentiviral short hairpin RNA (shSOCS3) (Lenti-shSOCS3) into the hematoma cavity at 24 h following ICH. We found that the number of iNOS-positive cells (M1 phenotype) was significantly reduced, whereas arginase-1-positive cells (M2 phenotype) were markedly elevated in animals that received Lenti-shSOCS3 injections compared with those in the Lenti-EGFP and saline groups. The increase in arginase-1-positive cells was associated with a significantly lower pro-inflammatory microenvironment, which included the downregulation of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, and TNF-α] and concurrent upregulation of anti-inflammatory (IL-10) mediators. In addition, this marked shift toward the M2 phenotype was associated with suppressed NF-κB activation. Furthermore, these changes notably enhanced the neuroprotective effects and functional recovery in Lenti-shSOCS3-injected animals. Our findings indicated that reduction in SOCS3 expression caused a marked bias toward the M2 phenotype and ameliorated the inflammatory microenvironment, which enhanced neuroprotective effects and resulted in notable improvement in functional recovery after ICH.

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Section: Discussionmentioning

confidence: 99%

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Shi

Zhang

et al. 2020

Front. Neurol.

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“…Several exogenous compounds and drugs are able to modulate microglial phenotype in experimental studies 77‐80 . For example, the naturally occurring chemical compound berberine may protect against ischemic stroke by modulating microglial polarization 77,78 .…”

Section: Microglial Polarization and Their Modulatory Mechanisms Aftementioning

confidence: 99%

Microglial/Macrophage polarization and function in brain injury and repair after stroke

et al. 2021

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Stroke is a leading cause of disability and mortality, with limited treatment options. After stroke injury, microglia and CNS‐resident macrophages are rapidly activated and regulate neuropathological processes to steer the course of functional recovery. To accelerate this recovery, microglia can engulf dying cells and clear irreparably‐damaged tissues, thereby creating a microenvironment that is more suitable for the formation of new neural circuitry. In addition, monocyte‐derived macrophages cross the compromised blood‐brain barrier to infiltrate the injured brain. The specific functions of myeloid lineage cells in brain injury and repair are diverse and dependent on phenotypic polarization statuses. However, it remains to be determined to what degree the CNS‐invading macrophages occupy different functional niches from CNS‐resident microglia. In this review, we describe the physiological characteristics and functions of microglia in the developing and adult brain. We also review (a) the activation and phenotypic polarization of microglia and macrophages after stroke, (b) molecular mechanisms that control polarization status, and (c) the contribution of microglia to brain pathology versus repair. Finally, we summarize current breakthroughs in therapeutic strategies that calibrate microglia/macrophage responses after stroke.

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“…The activation level of microglia is considered to be a marker of the severity of inflammation after CI/R injury ( Li et al, 2019 ) and this was quantified by Iba-1 immunofluorescence staining. A key characteristic of activated microglia following CI/R injury are their amoeba-like cell bodies ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Nuclear factor-kappa B (NF-kB) plays a central role in the pro-inflammatory function through the regulation of inflammatory cytokines after CI/R injury ( Li et al, 2019 ). HE has been reported to inactivate lipopolysaccharide-stimulated RAW 264.7 cells by inhibiting the NF-kB signalling pathway ( Lee et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Hederagenin Attenuates Cerebral Ischaemia/Reperfusion Injury by Regulating MLK3 Signalling

Song

Cao

et al. 2020

Front. Pharmacol.

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Cerebral ischaemia/reperfusion (CI/R) injury is a major challenge due to the lack of effective neuroprotective drugs. Hederagenin (HE) is the aglycone part of saponins extracted from Hedera helix Linné that has exhibited anti-apoptotic and anti-inflammatory effects; however, the role of HE in CI/R has not been elucidated. In this study, mice were intraperitoneally (i.p.) injected with HE (26.5, 53, or 106 μmol/kg body weight) for 3 days after middle cerebral artery occlusion (MCAO). Neural function and brain infarct volume were evaluated. HE treatment attenuated CI/R-induced apoptosis and inflammatory cytokine expression within the infarcted areas. HE treatment also decreased the activation of the MLK3 signalling pathway, which potentiates CI/R damage via the MAPK and NFκB pathways. Due to HE’s safety profile, it has potential to be used for the clinical treatment of ischaemic stroke.

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Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation

Cited by 63 publications

References 25 publications

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression Promotes M2 Macrophage Polarization and Functional Recovery After Intracerebral Hemorrhage

Microglial/Macrophage polarization and function in brain injury and repair after stroke

Hederagenin Attenuates Cerebral Ischaemia/Reperfusion Injury by Regulating MLK3 Signalling

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