Lysosomes, Lysosomal Storage Diseases, and Inflammation

Simonaro, Calogera M.

doi:10.1177/2326409816650465

Cited by 34 publications

(31 citation statements)

References 65 publications

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“…This fatal relationship is exemplified by lysosomal storage disorders (LSD) caused by hereditary dysfunctions of lysosomes which are accompanied by an abnormal activation of TLR4 and production of pro-inflammatory cytokines [238,239]. These responses can be triggered by an extracellular accumulation of undegraded substances which act as DAMPs and also by excessive TLR4 stability and persistent signaling caused by an impaired lysosomal proteolysis in cells of LSD patients.…”

Section: Contribution Of Abnormal Trafficking Of Tlr4 and Cd14 To Patmentioning

confidence: 99%

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

Ciesielska

Matyjek

Kwiatkowska

2020

Cell. Mol. Life Sci.

631

466

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Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.

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Section: Contribution Of Abnormal Trafficking Of Tlr4 and Cd14 To Patmentioning

confidence: 99%

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

Ciesielska

Matyjek

Kwiatkowska

2020

Cell. Mol. Life Sci.

631

466

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“…There are numerous studies demonstrating that widespread sub-lethal activation of the TNF-α, PARP-1 and NLRP3 signalling pathways, the presence of lysosomal dysfunction, iron accumulation, lipid peroxidation and downregulation of positive inhibitors of ferroptosis singly and collectively play a causative role in the pathophysiology and pathogenesis of many if not all neurodegenerative diseases [ 19 , 25 , 26 ]. Activation of PARP-1 signalling, the NLRP3 inflammasome, TNF-mediated inflammatory pathways, lysosomal dysfunction, lipid peroxidation and downregulation of positive inhibitors of ferroptosis have also been repeatedly demonstrated in neuroprogressive disorders [ 10 , 27 – 32 ]. There is also evidence of iron dyshomeostasis in MDD and BD [ 33 , 34 ], and researchers have previously observed cellular iron accumulation in at least some patients [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists

et al. 2017

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In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors (TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-α); poly [ADP-ribose] polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF-α-TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-α, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and N-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.

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“…This has essential consequences for the interpretation of the results. Endolysosomal storage of glucosylceramide and glucosylsphingosine affects the functionality of the lysosomes, which have an important role in the elimination of eobiotic compounds and inflammatory protection [ 23 ]. The recruitment of additional dysfunctional immune cells such as macrophages to the site of inflammation can accelerate disease progression, because the macrophages and neutrophils can no longer exert their protective role.…”

Section: Discussionmentioning

confidence: 99%

Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease

Lukáš

Cozma

Yang

et al. 2017

IJMS

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Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The build-up of glucosylceramide in the endoplasmic reticulum and prominent accumulation in cell lysosomes of tissue macrophages results in decreased blood cell and platelet counts, and skeletal abnormalities. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD. Mice received lyso-Gb1 at a dosage of 10 mg·kg−1 per day as a continuous subcutaneous administration, and were routinely checked for blood lyso-Gb1 levels using liquid chromatography-multiple reaction monitoring mass spectrometry (LC/MRM-MS) measurements at four-weekly intervals throughout treatment. The C57BL/6JRj mice showed a stable increase of lyso-Gb1 up to->500-fold greater than the normal reflecting concentrations seen in moderately to severely affected patients. Furthermore, lyso-Gb1 accumulated in peripheral tissues. The mice developed hematological symptoms such as reduced hemoglobin and hematocrit, increased spleen weights and a slight inflammatory tissue response after eight weeks of treatment. The above findings indicate a measurable visceral and hematological response in treated mice that suggests a role for lyso-Gb1 in the development of peripheral signs of GD.

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Lysosomes, Lysosomal Storage Diseases, and Inflammation

Cited by 34 publications

References 65 publications

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists

Glucosylsphingosine Causes Hematological and Visceral Changes in Mice—Evidence for a Pathophysiological Role in Gaucher Disease

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