Lysophosphatidylcholine activates caspase-1 in microglia via a novel pathway involving two inflammasomes

Scholz, Holger; Eder, Claudia

doi:10.1016/j.jneuroim.2017.07.004

Cited by 36 publications

(29 citation statements)

References 22 publications

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“…Recently, Freeman et al showed that LPC-induced IL-1β secretion in BMDMs is dependent on NLRC4, NLRP3, caspase-1, and ASC, whereas the non-canonical inflammasome-associated protein caspase-11 is not involved. In addition, LPC could induce NLRC4 and NLRP3 inflammasome activation in microglia and astrocytes in a caspase-1 activation-dependent manner (61,62). LPC can induce IL-1β release in human monocytes (45).…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells

et al. 2020

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Foam cells are specialized lipid-loaded macrophages derived from monocytes and are a key pathological feature of atherosclerotic lesions. Lysophosphatidylcholine (LPC) is a major lipid component of the plasma membrane with a broad spectrum of proinflammatory activities and plays a key role in atherosclerosis. However, the role of LPC in lipid droplet (LD) biogenesis and the modulation of inflammasome activation is still poorly understood. In the present study, we investigated whether LPC can induce foam cell formation through an analysis of LD biogenesis and determined whether the cell signaling involved in this process is mediated by the inflammasome activation pathway in human endothelial cells and monocytes. Our results showed that LPC induced foam cell formation in both types of cells by increasing LD biogenesis via a NLRP3 inflammasome-dependent pathway. Furthermore, LPC induced pyroptosis in both cells and the activation of the inflammasome with IL-1β secretion, which was dependent on potassium efflux and lysosomal damage in human monocytes. The present study described the IL-1β secretion and foam cell formation triggered by LPC via an inflammasome-mediated pathway in human monocytes and endothelial cells. Our results will help improve our understanding of the relationships among LPC, LD biogenesis, and NLRP3 inflammasome activation in the pathogenesis of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells

et al. 2020

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“…Saturated FA, ceramide, cardiolipin and lyso-PC, have been reported to act as second signal activators of the NLRP3 inflammasome [ 17 , 18 , 51 , 52 , 68 ]. In this study, lyso-PC was found to activate both adipocyte and ATM NLRP3 inflammasomes in autocrine and paracrine manners.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating Homocysteine-Induced Insulin Resistance

et al. 2018

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The adipose Nod-like receptor protein 3 (NLRP3) inflammasome senses danger-associated molecular patterns (DAMPs) and initiates insulin resistance, but the mechanisms of adipose inflammasome activation remains elusive. In this study, Homocysteine (Hcy) is revealed to be a DAMP that activates adipocyte NLRP3 inflammasomes, participating in insulin resistance. Hcy-induced activation of NLRP3 inflammasomes were observed in both adipocytes and adipose tissue macrophages (ATMs) and mediated insulin resistance. Lysophosphatidylcholine (lyso-PC) acted as a second signal activator, mediating Hcy-induced adipocyte NLRP3 inflammasome activation. Hcy elevated adipocyte lyso-PC generation in a hypoxia-inducible factor 1 (HIF1)-phospholipase A2 group 16 (PLA2G16) axis-dependent manner. Lyso-PC derived from the Hcy-induced adipocyte also activated ATM NLRP3 inflammasomes in a paracrine manner. This study demonstrated that Hcy activates adipose NLRP3 inflammasomes in an adipocyte lyso-PC-dependent manner and highlights the importance of the adipocyte NLRP3 inflammasome in insulin resistance.

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“…LPC acts on a number of immune target cells, for example, it upregulates cytokine production and chemotaxis in macrophages and T-lymphocytes [32][33][34][35] . It also activates caspase-1 in microglia in the brain neuroinflammatory process 36 . PAF is also a potent activator of inflammatory cells involved in the innate immune system, including neutrophils, macrophages and platelets.…”

Section: Detection Of Mitochondrial Dysfunction In Ftd Using Serum LImentioning

confidence: 99%

Uncovering pathophysiological changes in frontotemporal dementia using serum lipids

Phan

Pickford

Bhatia

et al. 2020

Sci Rep

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Blood serum is enriched in lipids and has provided a platform to understand the pathogenesis of a number of human diseases with improved diagnosis and development of biomarkers. Understanding lipid changes in neurodegenerative diseases is particularly important because of the fact that lipids make up >50% of brain tissues. Frontotemporal dementia (FTD) is a common cause of early onset dementia, characterized by brain atrophy in the frontal and temporal regions, concomitant loss of lipids and dyslipidemia. However, little is known about the link between dyslipidemia and FTD pathophysiology. Here, we utilized an innovative approach-lipidomics based on mass spectrometryto investigate three key aspects of FTD pathophysiology-mitochondrial dysfunction, inflammation, and oxidative stress. We analyzed the lipids that are intrinsically linked to neurodegeneration in serum collected from FTD patients and controls. We found that cardiolipin, acylcarnitine, lysophosphatidylcholine, platelet-activating factor, o-acyl-ω-hydroxy fatty acid and acrolein were specifically altered in FTD with strong correlation between the lipids, signifying pathophysiological changes in FTD. The lipid changes were verified by measurement of the common disease markers (e.g. ATP, cytokine, calcium) using conventional assays. When put together, these results support the use of lipidomics technology to detect pathophysiological changes in FTD. Lipidomics is a systems-level analysis and characterization of lipids 1,2. Like other "omics" analyses, such as transcriptomics and proteomics, lipidomics is a global profiling of lipid species present in cells, tissues or body fluids 3. Lipidomics allows detection and quantification of thousands of different lipid species of a broad range of lipid classes 4. It has facilitated a greater understanding of the pathophysiology of a range of human diseases, particularly cardiovascular disease and diabetes. It has also provided invaluable data to identify risk factors and develop biomarkers for disease identification and classification. Recent advances in lipidomics technology based on mass spectrometry have significantly improved the detection of a vast array of lipids present in blood serum. Importantly, it has allowed detection of small, yet significant, differences in lipid levels that are intrinsically linked to disease processes. Application of lipidomics in the study of neurodegenerative diseases is particularly imperative because of the fact that lipids make up 39.6% of the brain grey matter and 64.6% of the white matter 5. Frontotemporal dementia (FTD) is the second most common form of younger-onset dementia after Alzheimer's disease (AD), of which the main clinical syndrome is the behavioral variant (bvFTD) 6. Clinically, bvFTD is characterized by progressive changes in behavior and personality, loss of empathy, apathy, as well as variable cognitive deficits that include executive function, language and, in a subset episodic memory. Pathologically, FTD is characterized by brain atrophy in the frontal and ...

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Lysophosphatidylcholine activates caspase-1 in microglia via a novel pathway involving two inflammasomes

Cited by 36 publications

References 22 publications

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells

Lysophosphatidylcholine Induces NLRP3 Inflammasome-Mediated Foam Cell Formation and Pyroptosis in Human Monocytes and Endothelial Cells

Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating Homocysteine-Induced Insulin Resistance

Uncovering pathophysiological changes in frontotemporal dementia using serum lipids

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