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Inflammasome activation due to impaired autophagy in Gaucher macrophages (GMs) (1) In both control and GMs, lipopolysaccharide (LPS) priming induces activation of p65-NF-kB, which is translocated to the nucleus, leading to production of pro-IL-1β in the cytosol. In control macrophages (1a), LPS stimulates accumulation of ubiquitinated p65-NF-kB, which is further recognized by p62, delivered to autophagosomes, and degraded in the lysosome (1a, solid line). In GMs (1b, dashed line), impaired autophagy prevents degradation of p65- NF-kB through autophagy and results in its activation (1b). (2) In both control and GMs, stimulation by both LPS and extracellular ATP leads to inflammasome complex formation (NLRP3, apoptosis-associated speck-like proteins (ASC) and caspase1) and activation. (3) Activated inflammasomes undergo ubiquitination of ASC, leading to p62-mediated engulfment of inflammasomes by autophagosomes. Pro-IL-1β conversion to active IL-1β is limited due to the destruction of activated inflammasomes by autophagolysosomes. In GMs, defective autophagy and lysosomal dysfunction inhibit the elimination of active inflammasomes through autophagy, resulting in the upregulation and secretion of IL-1β (3).
Source publication
Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer-amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derive...
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Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophage...
Background
Neuronopathic Gaucher disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in GBA and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features; however, the role of GBA in individual cell types and involvement of microglia, blood-derived macrophages, and im...
Gaucher disease is a disorder of lysosomes caused by a functional defect of the glucocerebrosidase enzyme. The disease is mainly due to mutations in the GBA1 gene, which determines the gradual storage of glucosylceramide substrate in the patient's macrophages. In this paper, we describe the case of a 38-year-old man who clinically presented with hy...
Introduction:
Multiple myeloma (MM) is an incurable, biologically heterogeneous disease of the plasma cells, associated with older age and is more common in men. Gaucher disease, caused by mutation in acid β-glucosidase (glucocerebrosidase, GBA) gene, has been linked to multiple cancers, especially MM. Pathological accumulation of glucosylceramide...
Background:
Gaucher disease (GD) is an autosomal recessive disorder produced by mutations in the glucocerebrosidase gene (GBA), causing storage of glucosylceramide in reticuloendothelial cells in multiple organs. Traditionally, the prediction of the phenotype based on the genotype has been reported to be limited.
Subjects and methods:
We investi...
Citations
... Damaged organelles and cellular debris are not removed, leading to the accumulation of additional waste in the cytoplasm and overloading of lysosomes (10). The accumulation of waste becomes a stimulus for the inflammatory response, activating immune cells and exacerbating the systemic symptoms of GD (11). ...
Introduction and purpose: Gaucher's Disease (GD), a rare genetic disorder, is a difficult challenge in genetic and metabolic disorders. The aim of this review is to provide an exploration of GD, spanning its pathophysiology to the latest advancements in diagnostic and therapeutic innovations. In this review we aimed to underscore the challenges it presents and the ongoing efforts to overcome them. State of knowledge: GD, characterized by the accumulation of glucocerebroside, involves molecular, cellular, and systemic dysfunctions. At the molecular level, mutations in the GBA gene give rise to diverse manifestations, influencing disease severity. Cellular disruptions lead to lysosomal dysfunction, altered calcium homeostasis, and chronic inflammation, impacting various organ systems. Diagnostic approaches involve biomarkers, genetic testing, and imaging studies, each playing a crucial role in confirming the disease type and assessing its grade. Summary: Management and treatment strategies for GD have evolved, with enzyme replacement therapy and substrate reduction therapy serving as the basics. However, challenges persist, including limited efficacy in treating neurological symptoms and the high cost of treatments. The review highlights ongoing research and future perspectives in GD therapy.
... Sqstm1 is a promising mechanistic candidate in PIKfyve regulation as it is involved in vesicular trafficking, autophagy, and lysosome and proteasome degradation. 72,73 Importantly, Sqstm1 can regulate NF-κB activation under various conditions 72,[74][75][76] and is known to interact with TBK-1. 72,73,[77][78][79][80] Utilizing the TCGA Pan-Cancer data, we found that high SQSTM1 was associated with better overall survival in patients (Supp. ...
... 72,73 Importantly, Sqstm1 can regulate NF-κB activation under various conditions 72,[74][75][76] and is known to interact with TBK-1. 72,73,[77][78][79][80] Utilizing the TCGA Pan-Cancer data, we found that high SQSTM1 was associated with better overall survival in patients (Supp. 6a). ...
... 71,91,92 Furthermore, we identified SQSTM1, which has been shown to regulate NF-κB signaling under a wide range of conditions, as a possible mechanistic linchpin. 72,73,[77][78][79][80] As SQSTM1 is a critical component of autophagic regulation through TBK-1, 72,74-76 vesicle trafficking 72,73 , and transcriptional regulation, 73 it is a potential nexus between PIKfyve and alternate or non-canonical NF-κB regulation. In addition, we discovered that PIKfyve may preferentially alter cDC1s in tumor models. ...
The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-KB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
... Various mechanisms have been proposed for the beneficial effects of KD, including the modulation of inflammatory signaling pathways such as NF-κB [202], NLRP3 inflammasome [203,204], and the mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/ERK) pathway [205], all of which have been reported to be disturbed in FD [206,207], and other LDSs [208,209]. Additionally, KD has been associated with improved mitochondrial function and ATP production [210,211]. However, prolonged KD in some studies has been linked to reduced mitochondrial biogenesis and several health concerns, including cardiac complications and metabolic disturbances [212,213], emphasizing the need for more comprehensive research and careful application in long-term dietary interventions. ...
Purpose of Review
This review explores the interplay among metabolic dysfunction, oxidative stress, inflammation, and fibrosis in Fabry disease, focusing on their potential implications for cardiac involvement. We aim to discuss the biochemical processes that operate in parallel to sphingolipid accumulation and contribute to disease pathogenesis, emphasizing the importance of a comprehensive understanding of these processes.
Recent Findings
Beyond sphingolipid accumulation, emerging studies have revealed that mitochondrial dysfunction, oxidative stress, and chronic inflammation could be significant contributors to Fabry disease and cardiac involvement. These factors promote cardiac remodeling and fibrosis and may predispose Fabry patients to conduction disturbances, ventricular arrhythmias, and heart failure. While current treatments, such as enzyme replacement therapy and pharmacological chaperones, address disease progression and symptoms, their effectiveness is limited.
Summary
Our review uncovers the potential relationships among metabolic disturbances, oxidative stress, inflammation, and fibrosis in Fabry disease–related cardiac complications. Current findings suggest that beyond sphingolipid accumulation, other mechanisms may significantly contribute to disease pathogenesis. This prompts the exploration of innovative therapeutic strategies and underscores the importance of a holistic approach to understanding and managing Fabry disease.
... Multiple genetic studies have linked PD risk to immune-related pathways and pathogenic variants in immune genes (e.g., Toll-like receptor (TLR-4), Tumour Necrosis Factor (TNF)-α and Human Leukocyte Antigen-DR (HLA-DR) [10][11][12][13]. Furthermore, impaired autophagy in macrophages derived from peripheral monocytes of GD patients leads to increased secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-β in association with inflammasome activation [14]. Despite the growing evidence linking immune dysfunction to sporadic PD and GD, the precise role of immune responses in gut-brain cross-talk in GBA1-PD and neuronopathic GD is yet to be elucidated. ...
Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest known genetic risk factors for Parkinson’s disease (PD). Communication between the gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1 , display widespread NF -k B signalling activation, including gut inflammation, and brain glial activation. We also demonstrate intestinal autophagic defects, gut dysfunction, and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, partially ameliorates lifespan, locomotor and immune phenotypes. Moreover, we show that modulation of the immune deficiency (IMD) pathway is detrimental to the survival of Gba1 deficient flies. We also reveal that direct stimulation of autophagy by rapamycin treatment achieves similar benefits to germ-free conditions independent of gut bacterial load. Consistent with this, we show that pharmacologically blocking autophagosomal-lysosomal fusion, mimicking the autophagy defects of Gba1 depleted cells, is sufficient to stimulate intestinal immune activation. Overall, our data elucidate a mechanism whereby an altered microbiome, coupled with defects in autophagy, drive chronic activation of NF -k B signaling in a Gba1 loss-of-function model. It also highlights that elimination of the microbiota or stimulation of autophagy to remove immune mediators, rather than prolonged immunosuppression, may represent effective therapeutic avenues for GBA1- associated disorders.
... What is also worth noting is the importance of glucocerebrosidase (Gcase) in the process of autophagic cell death (as a positive mediator). The impairment of this process has the effect of inducing and sustaining the inflammatory process through constant inflammasome activation in human Gaucher macrophages [28,29]. Other hypotheses that might explain the relationship between Gaucher disease and lymphoproliferative disorders include disorders in intercellular transmission, e.g., the occurrence of a cytokine storm secretion of pro-and anti-flooded factors, cytokines/chemokines/hydrolases, or the influence of IL1/IL6, secreted by B lymphocytes, on the production of immunoglobulins [30][31][32]. ...
Hematological abnormalities are the most common early symptoms of Gaucher disease (GD), with an increased risk of hematopoietic system malignancies reported in patients with GD. GD may be associated with monoclonal and polyclonal gammopathies; however, the mechanism of association of GD with multiple myeloma (MM) remains uncertain. Enzyme replacement therapy (ERT) has been shown to improve patients’ cytopenia and it seems to facilitate anti-myeloma therapy in patients with co-occurring GD and MM. Although it is necessary to demonstrate the deficiency of enzymatic activity, as well as using genetic tests to finally diagnose GD, due to changes in the blood count image, bone marrow biopsy is still a frequent element of the GD diagnosis procedure. The diagnosis of GD is often delayed, mainly due to the heterogeneity of the histopathological picture of bone marrow biopsy or overlapping hematological abnormalities. Unrecognized and untreated GD worsens the response of a patient with an oncological disease to targeted treatment. We present a literature review, inspired by the case of a Caucasian patient initially diagnosed with MM and later confirmed with comorbid GD type 1 (GD1). We would like to point out the problem of underdiagnosis and delay in patients with GD.
... Lipid-laden macrophages or "Gaucher cells" infiltrate the bone marrow, spleen, 2 of 16 and liver, representing GD's hallmark [2]. Gaucher cells produce a peculiar signature of inflammatory genes [3]. ...
Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD.
... As known, non-inhibitory chaperones can facilitate GCase folding and assist it to translocate into lysosomes without interfering with the active center of the protein and thus can restore the enzyme activity. Promising GCase non-inhibitory PCs NCGC00241607 (NCGC607) and NCGC00188758 have been uncovered and investigated in vitro for GD1, GD2 and also for PD [18,[25][26][27][28][29][30][31]. However, binding sites on the enzyme surface for these PCs have not yet been identified. ...
Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson’s disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To date, NCGC00241607 (NCGC607) is one of the most promising PCs. Using molecular docking and molecular dynamics simulation we identified and characterized six allosteric binding sites on the GCase surface suitable for PCs. Two sites were energetically more preferable for NCGC607 and located nearby to the active site of the enzyme. We evaluated the effects of NCGC607 treatment on GCase activity and protein levels, glycolipids concentration in cultured macrophages from GD (n = 9) and GBA-PD (n = 5) patients as well as in induced human pluripotent stem cells (iPSC)—derived dopaminergic (DA) neurons from GBA-PD patient. The results showed that NCGC607 treatment increased GCase activity (by 1.3-fold) and protein levels (by 1.5-fold), decreased glycolipids concentration (by 4.0-fold) in cultured macrophages derived from GD patients and also enhanced GCase activity (by 1.5-fold) in cultured macrophages derived from GBA-PD patients with N370S mutation (p < 0.05). In iPSC-derived DA neurons from GBA-PD patients with N370S mutation NCGC607 treatment increased GCase activity and protein levels by 1.1-fold and 1.7-fold (p < 0.05). Thus, our results showed that NCGC607 could bind to allosteric sites on the GCase surface and confirmed its efficacy on cultured macrophages from GD and GBA-PD patients as well as on iPSC-derived DA neurons from GBA-PD patients.
... IL6 decreased in the first months of life to 13 nmol/L. Inflammasome activation seems to be due to impaired autophagy in Gaucher cells, suggesting a link between lysosomal dysfunction and inflammasome activation (Aflaki et al., 2016). Clinically, GD type 2 patients can also present persistent fevers, which may be due to the inflammatory component (Mignot et al., 2006). ...
... Specifically, in Gaucher disease, the accumulation of glucosylceramide and glucosylsphingosine in macrophage leads to macrophage activation-mediated release of various cytokines (i.e., chitotriosidase, TNF-a, IL-1b) (28), while there is also lysosomal dysfunction-mediated trigger of auto-inflammatory cascades involving a broad spectrum of myeloid cells, cytokine/chemokine secretion and NLRP3 inflammasome activation (23,32). Polyclonal and monoclonal gammopathies were also reported in Gaucher disease in addition to thrombocytopenia, disturbed hemostasis and spleen infarcts (28, [33][34][35]. ...
This expert-opinion-based document was prepared by a group of specialists in pediatric inherited metabolic diseases and infectious diseases including administrative board members of Turkish Society for Pediatric Nutrition and Metabolism to provide guidance for the care of children with lysosomal storage disorders (LSDs) during the COVID-19 pandemic in Turkey. The experts reached consensus on key areas of focus regarding COVID-19-based risk status in relation to intersecting immune-inflammatory mechanisms and disease patterns in children with LSDs, diagnostic virus testing, particularly preventive measures and priorities during the pandemic, routine screening and diagnostic interventions for LSDs, psychological and socioeconomic impact of confinement measures and quarantines and optimal practice patterns in managing LSDs and/or COVID-19. The participating experts agreed on the intersecting characteristics of immune-inflammatory mechanisms, end-organ damage and prognostic biomarkers in LSD and COVID-19 populations, emphasizing the likelihood of enhanced clinical care when their interaction is clarified via further studies addressing certain aspects related to immunity, lysosomal dysfunction and disease pathogenesis. In the context of the current global COVID-19 pandemic, this expert-opinion-based document provides guidance for the care of children with LSDs during the COVID-19 pandemic based on the recent experience in Turkey.
... Other authors have suggested that the chronic low-grade inflammation present in GD-1 may lead to dysregulation of ferroportin expression [116]. Studying macrophages derived from peripheral mononuclear cells from patients with type 1 Gaucher disease with genotype N370S/N370S, Aflaki et al. [120] found increased secretion of interleukins IL-1b and IL-6. They also demonstrated that impaired autophagy in Gaucher macrophages leads to inflammasome activation. ...
Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe2+, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy—all of which may elevate serum ferritin—complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia.
