Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke

Poh, Luting; Kang, Seok Woo; Baik, Sang‐Ha; Ng, Gee Wah; She, David T.; Balaganapathy, Priyanka; Dheen, S. Thameem; Magnus, Tim; Gelderblom, Mathias; Sobey, Christopher G.; Koo, Edward H.; Fann, David Y.; Arumugam, Thiruma V.

doi:10.1016/j.bbi.2018.09.001

Cited by 140 publications

(102 citation statements)

References 55 publications

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“…The functional implications of this process are still unknown. It is possible that induction of pyroptosis by DHA metabolites represents a novel initiating pattern of sterile inflammation in the CNS (Rubartelli et al 2013), for example, in ischemic stroke (Poh et al 2019). Alternatively, pyroptotic death of microglia may serve to limit chronic inflammation through loss of pro-inflammatory immune cells (Ortega-Gomez et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…This process is triggered by recognition of conserved microbial features by host pattern recognition receptors (PRRs) that are expressed by immune antigen-presenting cells of the monocyte/macrophage lineage (Liu and Lieberman 2017). This leads to activation of protein complexes known as inflammasomes (Poh et al 2019), and activation of inflammatory caspases, including caspase-1 and caspase-11 (caspase-4/-5 in humans) (Miao et al 2011;Shi et al 2014). The result is cleavage of a cellular substrate called gasdermin D (GSDMD) to produce an N-terminal fragment capable of forming pores in the plasma membrane (Aglietti et al 2016;Ding et al 2016;Liu et al 2016;Sborgi et al 2016).…”

mentioning

confidence: 99%

“…Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host's defensive responses. Besides being an important component of the innate immune system, pyroptosis has also been shown to be involved in sterile inflammatory processes (Barrington et al 2017;Poh et al 2019).…”

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confidence: 99%

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Ultrastructural Characteristics of DHA-Induced Pyroptosis

et al. 2020

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Microglial cells are resident macrophages of the central nervous system (CNS) that respond to bioactive lipids such as docosahexaenoic acid (DHA). Low micromolar concentrations of DHA typically promote anti-inflammatory functions of microglia, but higher concentrations result in a form of pro-inflammatory programmed cell death known as pyroptosis. This study used scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to investigate the morphological characteristics of pyroptosis in BV-2 microglial cells following exposure to 200 µM DHA. Vehicle-treated cells are characterized by extended processes, spine-like projections or 0.4 to 5.2 µm in length, and numerous extracellular vesicles (EVs) tethered to the surface of the plasma membrane. In contrast to vehicle-treated cells, gross abnormalities are observed after treating cells with 200 µM DHA for 4 h. These include the appearance of numerous pits or pores of varying sizes across the cell surface, structural collapse and flattening of the cell shape. Moreover, EVs and spines were lost following DHA treatment, possibly due to release from the cell surface. The membrane pores appear after DHA treatment initially measured ~ 30 nm, consistent with the previously reported gasdermin D (GSDMD) pore complexes. Complete collapse of cytoplasmic organization and loss of nuclear envelope integrity were also observed in DHA-treated cells. These processes are morphologically distinct from the changes that occur during cisplatin-induced apoptosis, such as the appearance of apoptotic bodies and tightly packed organelles, and the maintenance of EVs and nuclear envelope integrity. Cumulatively, this study provides a systematic description of the ultrastructural characteristics of DHA-induced pyroptosis, including distinguishing features that differentiate this process from apoptosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Ultrastructural Characteristics of DHA-Induced Pyroptosis

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“…Microglia, the major cellular contributor to postinjury inflammation, have the potential to act as a key factor of disease onset and progression and to contribute to the neurological outcome of acute brain injury [48]. Under pathological conditions, microglia are rapidly activated and undergo dramatic morphological and phenotypic changes accompanied by the induction of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

Wang

Liu

Zhu

et al. 2020

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Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion：In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment. Keywords : rhFGF21, stroke, neuroinflammation, microglia/macrophage, NF-κB, PPAR-γ

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“…Microglia are major cellular contributor to postinjury in ammation and have the potential to act as a key factor for disease onset and progression and contribute to the neurological outcome of acute brain injury [50]. Under pathological conditions, microglia are rapidly activated and undergo dramatic morphological and phenotypic changes accompanied by the induction of in ammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

Wang

Liu

Zhu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion： In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.

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Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke

Cited by 140 publications

References 55 publications

Ultrastructural Characteristics of DHA-Induced Pyroptosis

Ultrastructural Characteristics of DHA-Induced Pyroptosis

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

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