Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice

Azambuja, Amanda Stapenhorst; Pimentel-Vera, Luisa N.; Gonzalez, Esteban Alberto; Poletto, Édina; Pinheiro, Camila Vieira; Matte, Úrsula da Silveira; Giugliani, Roberto; Baldo, Guilherme

doi:10.1007/s11011-020-00592-5

Cited by 13 publications

(8 citation statements)

References 23 publications

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“…Gonzalez and colleagues have already demonstrated an overexpression of cathepsin B in MPS I mice (Gonzalez et al, 2018). In addition to that, Azambuja et al (2020) observed in MPS II high levels of cathepsin B in the brain tissue and a leakage of the enzyme IDS, which is a known activator of the inflammasome. Furthermore, the author studied MPS II mice brains and demonstrated elevated activity of Caspase-1 and IL-1β, confirming that this pathway is indeed altered.…”

Section: Inflammatory Immune Responsesmentioning

confidence: 83%

“…Impaired autophagy appears to be associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated kinase (AMPK) signaling (Lim et al, 2017;Pasquale et al, 2020;Stepien et al, 2020). It has been proven that autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation and it has been extensively proven that there is a progressive block of autophagy in lysosomal storage disorders, including MPS (Azambuja et al, 2020). Furthermore, it has been observed that IL-1β and TNF-α correlate with each other.…”

Section: Inflammatory Immune Responsesmentioning

confidence: 99%

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The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

et al. 2022

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Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).

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Section: Inflammatory Immune Responsesmentioning

confidence: 83%

Section: Inflammatory Immune Responsesmentioning

confidence: 99%

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

et al. 2022

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“…The fact that there were ongoing, progressive airway abnormalities in our study despite consistent use of ERT likely indicates additional mechanisms of injury apart from cellular GAG deposition. This includes uncontrolled inflammation and tissue remodeling due to alterations in signal transduction [ 17 , 18 , 19 ], aberrations in immune function [ 20 ], activation of inflammatory cascades [ 21 ], and abnormal oxidative stress [ 22 , 23 ]. Further studies into the mechanisms of progressive airway deterioration despite ERT are warranted.…”

Section: Discussionmentioning

confidence: 99%

Airway Findings in Patients with Hunter Syndrome Treated with Intravenous Idursulfase

Vuyst

Jalazo

Tsujimoto³

et al. 2023

JCM

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People with Hunter syndrome are known to be affected by a variety of airway pathologies. Treatment of Hunter syndrome with the enzyme replacement therapy (ERT) idursulfase is now the standard of care. However, it is not known how ERT changes the progression of airway involvement. To evaluate this, we performed a retrospective analysis of bronchoscopies performed on children with Hunter syndrome who were part of intrathecal ERT trials. Findings for airway pathology were extracted from bronchoscopy reports and analyses were performed for cross-sectional and longitudinal changes in airway disease. One-hundred and thirty bronchoscopies from 23 subjects were analyzed. Upper airway disease (adenoid hypertrophy and/or pharyngomalacia) was reported in 93% and 87% of bronchoscopies, respectively. Laryngeal abnormalities were recognized in 46% of cases. There were lower airway (tracheal and or bronchial) findings in 64% of all bronchoscopies and prevalence increased with age. Evaluations over time adjusted for repeat evaluations showed that increasing airway involvement was associated with older age (p = 0.0007) despite ongoing ERT. No association was discovered between age of intravenous ERT initiation and progression of airway disease. Individuals with Hunter syndrome who are receiving intravenous enzyme replacement therapy showed the progression of airways disease supporting the need for regular airway monitoring and intervention.

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“…Cathepsin B may participate in the inflammasome-dependent pathway involved in neuroinflammation observed in the different types of MPS [ 92 ], while both cathepsins B and S may contribute to the progression of neurodegeneration in MPS-I and -IIIB [ 88 , 90 ]. An increase of cathepsin B activity was observed in the brain tissue of MPS-II mice [ 93 ]. Cathepsin B inhibition prevented neuronal death and behavioral disorders in a patient with Niemann–Pick type A disease and in an acid sphingomyelinase knockout mouse model [ 94 ].…”

Section: Cysteine Cathepsinsmentioning

confidence: 99%

The Interplay of Glycosaminoglycans and Cysteine Cathepsins in Mucopolysaccharidosis

et al. 2023

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Mucopolysaccharidosis (MPS) consists of a group of inherited lysosomal storage disorders that are caused by a defect of certain enzymes that participate in the metabolism of glycosaminoglycans (GAGs). The abnormal accumulation of GAGs leads to progressive dysfunctions in various tissues and organs during childhood, contributing to premature death. As the current therapies are limited and inefficient, exploring the molecular mechanisms of the pathology is thus required to address the unmet needs of MPS patients to improve their quality of life. Lysosomal cysteine cathepsins are a family of proteases that play key roles in numerous physiological processes. Dysregulation of cysteine cathepsins expression and activity can be frequently observed in many human diseases, including MPS. This review summarizes the basic knowledge on MPS disorders and their current management and focuses on GAGs and cysteine cathepsins expression in MPS, as well their interplay, which may lead to the development of MPS-associated disorders.

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Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice

Cited by 13 publications

References 23 publications

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy

Airway Findings in Patients with Hunter Syndrome Treated with Intravenous Idursulfase

The Interplay of Glycosaminoglycans and Cysteine Cathepsins in Mucopolysaccharidosis

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