Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome

Shu, Xiaoqiu; Chen, Wei; Tu, Wen-Yo; Zhong, Keke; Su, Qi; Wang, Ailian; Bai, Lei; Zhang, Shan-Xin; Luo, Benyan; Xu, Zhen-Zhong; Zhang, Kejing; Shen, Chengyong

doi:10.1016/j.celrep.2023.112133

Cited by 9 publications

(5 citation statements)

References 78 publications

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“…Recently, Shu et al also reported that GA-DPR can activate the NLRP3 inflammasome in mouse brain microglial cells, but they did not explore the mechanism of NLRP3 inflammasome activation. They found that aberrant NLRP3 inflammasome activity enhances ADAM10mediated TREM2 cleavage, leading to the inhibition of GA-DPR phagocytosis [54]. In addition, we found that GA 50 also induces apoptosis in HMC3 cells in addition to the pyroptosis induced by NLRP3 inflammasome activation.…”

Section: Discussionsupporting

confidence: 55%

“…Therefore, in addition to diminishing the activity of the NLRP3 inflammasome induced by GA 50 , IFT may also have neuroprotective activities in regulating cellular anti-oxidation, anti-inflammation, and clearing amyloid in C9-ALS patients. Several studies have shown that the inhibitor of the NLRP3 inflammasome (MCC950) can effectively reverse the motor deficits in ALS-containing GA-DPR-expressing mice caused by the activation of the NLRP3 inflammasome [54]. However, this non-specific broad inhibition of NLRP3 inflammasome activity may disrupt innate immune mechanisms and increase the chances of infection in patients.…”

Section: Discussionmentioning

confidence: 99%

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Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Fu,

Chen,

Hong

2023

Antioxidants

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Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA50) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA50 interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA50, thus inhibiting NLRP3 inflammasome activity in GA50-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Fu,

Chen,

Hong

2023

Antioxidants

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“…Our studies illustrate an unexpected finding that the TREM2 and MS4A7 pathways apparently exert opposing effects in shaping the inflammatory properties of NAMs in the liver during the progression of MASH. Recent work demonstrates that activation of NLRP3 inflammasome promotes ectodomain cleavage of TREM2 ( 52 ). It is therefore possible that MS4A7 may antagonize TREM2 function via an inflammasome-mediated mechanism.…”

Section: Discussionmentioning

confidence: 99%

Hepatic danger signaling triggers TREM2 ⁺ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation

Zhou,

Qiu,

Meng

et al. 2024

Sci. Transl. Med.

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Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2 + macrophages in various disease conditions, and substantial induction of TREM2 + NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2 + macrophages in disease pathogenesis.

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“…For example, components of the NLRP3 inflammasome complex were found to be upregulated in the skeletal muscle [ 60 ], spinal cord [ 59 ], and brain [ 62 , 63 ] of SOD1 animal models. Moreover, NLRP3 inflammasome activation was detected in in vitro ALS models of TDP-43 [ 64 ] and C9Orf72 [ 65 , 66 , 67 ]. However, until now, NLRP3 inflammasome activation has not been investigated in wobbler mice, the only naturally occurring sALS animal model.…”

Section: Discussionmentioning

confidence: 99%

Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS

Cihankaya,

Bader,

Winklhofer

et al. 2024

Cells

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 (CASP 1) auto-activation, leading to the cleavage of Gasdermin D (GSDMD) and pore formation on the cellular membrane. This process facilitates cytokine secretion and ultimately results in pyroptotic cell death, highlighting the complex interplay of inflammation and neurodegeneration in ALS. This study aimed to characterize the NLRP3 inflammasome components and their colocalization with cellular markers using the wobbler mouse as an ALS animal model. Firstly, we checked the levels of miR-223-3p because of its association with NLRP3 inflammasome activity. The wobbler mice showed an increased expression of miR-223-3p in the ventral horn, spinal cord, and cerebellum tissues. Next, increased levels of NLRP3, pro-CASP 1, cleaved CASP 1 (c-CASP 1), full-length GSDMD, and cleaved GDSMD revealed NLRP3 inflammasome activation in wobbler spinal cords, but not in the cerebellum. Furthermore, we investigated the colocalization of the aforementioned proteins with neurons, microglia, and astrocyte markers in the spinal cord tissue. Evidently, the wobbler mice displayed microgliosis, astrogliosis, and motor neuron degeneration in this tissue. Additionally, we showed the upregulation of protein levels and the colocalization of NLRP3, c-CASP1, and GSDMD in neurons, as well as in microglia and astrocytes. Overall, this study demonstrated the involvement of NLRP3 inflammasome activation and pyroptotic cell death in the spinal cord tissue of wobbler mice, which could further exacerbate the motor neuron degeneration and neuroinflammation in this ALS mouse model.

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Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome

Cited by 9 publications

References 78 publications

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Hepatic danger signaling triggers TREM2 ⁺ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation

Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS

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Negative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome

Cited by 9 publications

References 78 publications

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Hepatic danger signaling triggers TREM2 + macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation

Elevated NLRP3 Inflammasome Activation Is Associated with Motor Neuron Degeneration in ALS

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Resources

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Hepatic danger signaling triggers TREM2 ⁺ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation