scholarly journals The Expression of Chemokines Is Downregulated in a Pre-Clinical Model of TTR V30M Amyloidosis

2021 ◽  
Vol 12 ◽  
Author(s):  
João Moreira ◽  
Susete Costelha ◽  
Margarida Saraiva ◽  
Maria João Saraiva
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Neurodegenerative Disorder ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Transthyretin Amyloidosis ◽  
Clinical Model ◽  
Shed Light ◽  
Stimulation Of

Inflammation is a hallmark of several neurodegenerative disorders including hereditary amyloidogenic transthyretin amyloidosis (ATTRv). ATTRv is an autosomal dominant neurodegenerative disorder with extracellular deposition of mutant transthyretin (TTR) aggregates and fibrils, particularly in nerves and ganglia of the peripheral nervous system. Nerve biopsies from ATTRv patients show increased cytokine production, but interestingly no immune inflammatory cellular infiltrate is observed around TTR aggregates. Here we show that as compared to Wild Type (WT) animals, the expression of several chemokines is highly downregulated in the peripheral nervous system of a mouse model of the disease. Interestingly, we found that stimulation of mouse Schwann cells (SCs) with WT TTR results in the secretion of several chemokines, a process that is mediated by toll-like receptor 4 (TLR4). In contrast, the secretion of all tested chemokines is compromised upon stimulation of SCs with mutant TTR (V30M), suggesting that V30M TTR fails to activate TLR4 signaling. Altogether, our data shed light into a previously unappreciated mechanism linking TTR activation of SCs and possibly underlying the lack of inflammatory response observed in the peripheral nervous system of ATTRv patients.

scholarly journals Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

2012 ◽  
Vol 117 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Willem-Jan M. Schellekens ◽  
Hieronymus W. H. van Hees ◽  
Michiel Vaneker ◽  
Marianne Linkels ◽  
P. N. Richard Dekhuijzen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Caspase 3 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Diaphragm Atrophy ◽  
Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

Neurofilaments and pathologies of the Peripheral Nervous System

2014 ◽  
Author(s):  
◽  
Jeffrey Dale
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Conduction Velocity ◽  
Radial Growth ◽  
Stride Length ◽  
Wild Type ◽  
Axon Diameter ◽  
Internodal Length ◽  
Axonal Diameter ◽  
Myelin Thickness

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The efficiency of signal propagation in the peripheral nervous system (PNS) is maximized by myelination and axon diameter. Myelination induces axonal expansion through radial growth. Radial growth is dependent on neurofilaments (NFs) that can be made up of the neurofilament light (NF-L) subunit in association with either the neurofilament medium (NF-M) or neurofilament heavy (NF-H) subunit. Myelin thickness and length (internodal) are established proportional to axon diameter for optimal conduction velocity. Myelin thickness is regulated by total neuregulin I type III (Nrg1 type III) levels present on the axon whereas the mechanisms that control the establishment of internodal length are less understood. My work expands on previous data demonstrating that myelin thickness does not respond to alterations in axonal diameter. In contrast to the previous study, my work describes myelin thickness in the context of decreased axonal diameters. NF subunit mutants that result in varying degrees of altered axonal diameter were used as a tool to study the response of myelin thickness to larger reductions in axonal diameter. At two and six months, g-ratios corresponded to the degree of axonal diameter change. At two months, the size of axons arranged into the following order: wild type > NF-H[superscript [[delta]]Tail] > NF-M[superscript [[delta]]Tail]>NF-(M/H) [superscript [[delta]]Tail]. Correspondingly, g-ratios arranged into the same order indicating the larger the decrease in axon diameter, the greater the proportional increase in myelin thickness. At six months, axon diameters grouped into "wild type" sizes and "NFM?Tail" sizes. Similarly, g-ratios grouped into "wild type" ratios and "NF-M?Tail" ratios indicating that myelin thickness did not respond to increased radial growth. At six months NF-M?Tail mice demonstrated decreased internodal length suggesting that internodal length responded to alterations in axon diameter. My work provides the first evidence of the consequence of altered myelin thickness in isolation. Mice with hypomyelination, alone, demonstrated reduced swing speed and stride length in all limbs. Mutations in proteins specific to myelin result CMT1 that display uniform slowing of conduction velocity. In contrast, CMT2E arises from mutations to axonal proteins resulting in non-uniform slowing of conduction velocity. We generated a mouse model of CMT2E by expressing a hNF-L[superscript E397K] transgene. hNF-L[superscript E397K] expression causes inherent defects to the neurofilament network. As a result, our CMT2E model demonstrates altered myelin thickness in motor and sensory nerves and unilateral gait alterations that include decreased stride length, increased foot drags, and altered coordination of coupled limbs. The correlation between defects observed in our hypomyelination model and our CMT2E model suggest that altered myelin thickness may play a role in CMT2E phenotype. NF accumulations first appear at the NMJs of the diaphragm in SMA?7 mice. Motor axon loss and decreased axonal diameter is observed in the cervical spinal cord which is responsible for innervating the diaphragm. Taken together, these data suggest that inherent NF defects may be present in SMA?7 mice. My work provides a comprehensive analysis of the NF network in a cell, sciatic nerve, where analyses wouldn't be confounded by axonal loss. My analyses demonstrated that total NF levels, trafficking, and deposition were unaffected in SMA?7 mice suggesting that the NF network was uncompromised. Therefore, NF accumulations at the NMJ are most likely due to local alterations to NF dynamics. Furthermore, my work demonstrates that alterations to the transport of retrograde motors and anterograde transport of vital synaptic vesicle proteins coincide with the appearance of NF accumulations.

Monosodium urate crystal interleukin-1β release is dependent on Toll-like receptor 4 and transient receptor potential V1 activation

Rheumatology ◽  
2019 ◽  
Author(s):  
Mateus F. Rossato ◽  
Carin Hoffmeister ◽  
Gabriela Trevisan ◽  
Fabio Bezerra ◽  
Thiago M. Cunha ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Synovial Fluid ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Acute Gout ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Transient Receptor ◽  
Nitrite Nitrate

AbstractObjectiveThe present study aimed to elucidate the mechanisms involved in MSU-induced IL-1β release in a rodent animal model of acute gout arthritis.MethodsPainful (mechanical and thermal hypersensitivity, ongoing pain and arthritis score) and inflammatory (oedema, plasma extravasation, cell infiltration and IL-1β release) parameters were assessed several hours after intra-articular injection of MSU (100 µg/articulation) in wild-type or knockout mice for Toll-like receptor 4 (TLR4), inducible nitric oxide synthase (iNOS), transient receptor potential (TRP) V1 and the IL-1 receptor (IL-1R). Also, wild-type animals were treated with clodronate, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) (TLR4 antagonist), spleen tyrosine kinase (SYK) inhibitor (iSYK), aminoguanidine (AMG, an iNOS inhibitor) or SB366791 (TRPV1 antagonist). Nitrite/nitrate and IL-1β levels were measured on the synovial fluid of wild-type mice, 2 h after intra-articular MSU injections, or medium from macrophages stimulated for MSU (1000 μg) for 2 h.ResultsIntra-articular MSU injection caused robust nociception and severe inflammation from 2 up to 6 h after injection, which were prevented by the pre-treatment with clodronate, LPS-RS, iSYK, AMG and SB366791, or the genetic ablation of TLR4, iNOS, TRPV1 or IL-1R. MSU also increased nitrite/nitrate and IL-1β levels in the synovial fluid, which was prevented by clodronate, LPS-RS, iSYK and AMG, but not by SB366791. Similarly, MSU-stimulated peritoneal macrophages released nitric oxide, which was prevented by LPS-RS, iSYK and AMG, but not by SB366791, and released IL-1β, which was prevented by LPS-RS, iSYK, AMG and SB366791.ConclusionOur data indicate that MSU may activate TLR4, SYK, iNOS and TRPV1 to induce the release of IL-1β by macrophages, triggering nociception and inflammation during acute gout attack.

scholarly journals The Rotenone Models Reproducing Central and Peripheral Features of Parkinson’s Disease

NeuroSci ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. 1-14
Author(s):  
Ikuko Miyazaki ◽  
Masato Asanuma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Neurodegenerative Disorder ◽  
Rem Sleep Behavior Disorder ◽  
Experimental Models ◽  
Motor Symptoms ◽  
Sleep Behavior ◽  
Disease Modifying Drugs

Parkinson’s disease (PD) is a complex, multi-system, neurodegenerative disorder; PD patients exhibit motor symptoms (such as akinesia/bradykinesia, tremor, rigidity, and postural instability) due to a loss of nigrostriatal dopaminergic neurons, and non-motor symptoms such as hyposmia, autonomic disturbance, depression, and REM sleep behavior disorder (RBD), which precedes motor symptoms. Pathologically, α-synuclein deposition is observed in the central and peripheral nervous system of sporadic PD patients. To clarify the mechanism of neurodegeneration in PD and to develop treatment to slow or stop PD progression, there is a great need for experimental models which reproduce neurological features of PD. Animal models exposed to rotenone, a commonly used pesticide, have received most attention since Greenamyre and his colleagues reported that chronic exposure to rotenone could reproduce the anatomical, neurochemical, behavioral, and neuropathological features of PD. In addition, recent studies demonstrated that rotenone induced neuropathological change not only in the central nervous system but also in the peripheral nervous system in animals. In this article, we review rotenone models especially focused on reproducibility of central and peripheral multiple features of PD. This review also highlights utility of rotenone models for investigation of PD pathogenesis and development of disease-modifying drugs for PD in future.

Stimulation of the Extraspinal Peripheral Nervous System

2016 ◽  
pp. 171-183 ◽  
Author(s):  
W. Porter McRoberts ◽  
Timothy R. Deer ◽  
David Abejón ◽  
Giancarlo Barolat
Keyword(s):  
Nervous System ◽  
Peripheral Nervous System ◽  
Stimulation Of

The phytosphingosine-CD300b interaction promotes zymosan-induced, nitric oxide–dependent neutrophil recruitment

2019 ◽  
Vol 12 (564) ◽  
pp. eaar5514 ◽  
Author(s):  
Mariko Takahashi ◽  
Kumi Izawa ◽  
Makoto Urai ◽  
Yoshinori Yamanishi ◽  
Akie Maehara ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Neutrophil Recruitment ◽  
No Production ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Toll Like Receptor 4 ◽  
Potential Ligand ◽  
Inflammatory Dendritic Cells

Zymosan is a glucan that is a component of the yeast cell wall. Here, we determined the mechanisms underlying the zymosan-induced accumulation of neutrophils in mice. Loss of the receptor CD300b reduced the number of neutrophils recruited to dorsal air pouches in response to zymosan, but not in response to lipopolysaccharide (LPS), a bacterial membrane component recognized by Toll-like receptor 4 (TLR4). An inhibitor of nitric oxide (NO) synthesis reduced the number of neutrophils in the zymosan-treated air pouches of wild-type mice to an amount comparable to that inCD300b−/−mice. Treatment with clodronate liposomes decreased the number of NO-producing, CD300b+inflammatory dendritic cells (DCs) in wild-type mice, thus decreasing NO production and neutrophil recruitment. Similarly, CD300b deficiency decreased the NO-dependent recruitment of neutrophils to zymosan-treated joint cavities, thus ameliorating subsequent arthritis. We identified phytosphingosine, a lipid component of zymosan, as a potential ligand of CD300b. Phytosphingosine stimulated NO production in inflammatory DCs and promoted neutrophil recruitment in a CD300b-dependent manner. Together, these results suggest that the phytosphingosine-CD300b interaction promotes zymosan-dependent neutrophil accumulation by inducing NO production by inflammatory DCs and that CD300b may contribute to antifungal immunity.

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