Toll-like receptors 4, 5, 6 and 7 are constitutively expressed in non-human primate retinal neurons

Sauter, Monica M.; Kolb, Aaron W.; Brandt, Curtis R.

doi:10.1016/j.jneuroim.2018.06.007

Cited by 10 publications

(8 citation statements)

References 56 publications

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“…In the CNS, TLR2 and TLR4 are primarily expressed on astrocytes and microglia ( 29 , 38 ), but are also present on neurons ( 38 , 39 ) and CNS infiltrating T cells ( 40 , 41 ). Toll-like receptor 2 and 4 are activated by DAMPs from breakdown of myelin and other damaged and inflamed cells, including products such as heat shock protein 60 (HSP60), HSP70, high mobility group box 1 (HMGB1), alpha-synuclein, hyaluronic acid, fibrinogen, and biglycan ( 61 , 73 , 80 – 86 ).…”

Section: Discussionmentioning

confidence: 99%

“…Toll-like receptors 2 and 4 antagonists are one promising strategy to treat pain from MS ( 16 ), as well as neuropathic pain from both peripheral and central origin ( 34 – 37 ). Toll-like receptors 2 and 4 are commonly expressed on glial cells ( 29 , 38 ) as well as less commonly on neurons ( 38 , 39 ) and T cells ( 40 , 41 ). Importantly, TLR2–TLR4s are upregulated in white matter of patients with MS ( 42 – 44 ) as well as in EAE ( 42 – 45 ).…”

Section: Introductionmentioning

confidence: 99%

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Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Kwilasz¹,

Clements²,

Larson³

et al. 2022

Front. Pain Res.

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Up to 92% of patients suffering from multiple sclerosis (MS) experience pain, most without adequate treatment, and many report pain long before motor symptoms associated with MS diagnosis. In the most commonly studied rodent model of MS, experimental autoimmune encephalomyelitis (EAE), motor impairments/disabilities caused by EAE can interfere with pain testing. In this study, we characterize a novel low-dose myelin-oligodendrocyte-glycoprotein (MOG)-induced Sprague-Dawley (SD) model of EAE-related pain in male rats, optimized to minimize motor impairments/disabilities. Adult male SD rats were treated with increasing doses of intradermal myelin-oligodendrocyte-glycoprotein (MOG1−125) (0, 4, 8, and 16 μg) in incomplete Freund's adjuvant (IFA) vehicle to induce mild EAE. Von Frey testing and motor assessments were conducted prior to EAE induction and then weekly thereafter to assess EAE-induced pain and motor impairment. Results from these studies demonstrated that doses of 8 and 16 μg MOG1−125 were sufficient to produce stable mechanical allodynia for up to 1 month in the absence of hindpaw motor impairments/disabilities. In the follow-up studies, these doses of MOG1−125, were administered to create allodynia in the absence of confounded motor impairments. Then, 2 weeks later, rats began daily subcutaneous injections of the Toll-like receptor 2 and 4 (TLR2–TLR4) antagonist (+)-naltrexone [(+)-NTX] or saline for an additional 13 days. We found that (+)-NTX also reverses EAE-induced mechanical allodynia in the MOG-induced SD rat model of EAE, supporting parallels between models, but now allowing a protracted timecourse to be examined completely free of motor confounds. Exploring further mechanisms, we demonstrated that both spinal NOD-like receptor protein 3 (NLRP3) and interleukin-17 (IL-17) are necessary for EAE-induced pain, as intrathecal injections of NLRP3 antagonist MCC950 and IL-17 neutralizing antibody both acutely reversed EAE-induced pain. Finally, we show that spinal glial immunoreactivity induced by EAE is reversed by (+)-NTX, and that spinal demyelination correlates with the severity of motor impairments/disabilities. These findings characterize an optimized MOG-induced SD rat model of EAE for the study of pain with minimal motor impairments/disabilities. Finally, these studies support the role of TLR2–TLR4 antagonists as a potential treatment for MS-related pain and other pain and inflammatory-related disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Kwilasz¹,

Clements²,

Larson³

et al. 2022

Front. Pain Res.

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“…Interestingly, studies have demonstrated that mammalian TLRs and their Drosophila homologs trigger cell-autonomous processes independent of ligand activation during embryogenesis [ 3 ] and adult neurogenesis [ 6 – 8 ]. Constitutive expression of several TLR family members occurs in astrocytes [ 9 ], oligodendrocytes [ 10 ], neurons [ 11 , 12 ], and neural precursor cells (NPCs) [ 13 ]. Additionally, recent research has suggested a role for TLR2 and TLR4 in supporting neuronal morphogenesis and plasticity under physiological [ 3 , 7 ] and pathological conditions [ 14 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptors 2 and 4 differentially regulate the self-renewal and differentiation of spinal cord neural precursor cells

2022

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Background Toll-like receptors (TLRs) represent critical effectors in the host defense response against various pathogens; however, their known function during development has also highlighted a potential role in cell fate determination and neural differentiation. While glial cells and neural precursor cells (NPCs) of the spinal cord express both TLR2 and TLR4, their influence on self-renewal and cell differentiation remains incompletely described. Methods TLR2, TLR4 knock-out and the wild type mice were employed for spinal cord tissue analysis and NPCs isolation at early post-natal stage. Sox2, FoxJ1 and Ki67 expression among others served to identify the undifferentiated and proliferative NPCs; GFAP, Olig2 and β-III-tubulin markers served to identify astrocytes, oligodendrocytes and neurons respectively after NPC spontaneous differentiation. Multiple comparisons were analyzed using one-way ANOVA, with appropriate corrections such as Tukey's post hoc tests used for comparisons. Results We discovered that the deletion of TLR2 or TLR4 significantly reduced the number of Sox2-expressing NPCs in the neonatal mouse spinal cord. While TLR2-knockout NPCs displayed enhanced self-renewal, increased proliferation and apoptosis, and delayed neural differentiation, the absence of TLR4 promoted the neural differentiation of NPCs without affecting proliferation, producing long projecting neurons. TLR4 knock-out NPCs showed significantly higher expression of Neurogenin1, that would be involved in the activation of this neurogenic program by a ligand and microenvironment-independent mechanism. Interestingly, the absence of both TLR2 and TLR4, which induces also a significant reduction in the expression of TLR1, in NPCs impeded oligodendrocyte precursor cell maturation to a similar degree. Conclusions Our data suggest that Toll-like receptors are needed to maintain Sox2 positive neural progenitors in the spinal cord, however possess distinct regulatory roles in mouse neonatal spinal cord NPCs—while TLR2 and TLR4 play a similar role in oligodendrocytic differentiation, they differentially influence neural differentiation.

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“…Interestingly, studies have demonstrated that mammalian TLRs and their Drosophila homologs trigger cell-autonomous processes independent of ligand activation during embryogenesis [3] and adult neurogenesis [6][7][8]. Constitutive expression of several TLR family members occurs in astrocytes [9], oligodendrocytes [10], neurons [11,12], and neural precursor cells (NPCs) [13]. Additionally, recent research has suggested a role for TLR2 and TLR4 in supporting neuronal morphogenesis and plasticity under physiological [3,7] and pathological conditions [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptors 2 and 4 Differentially Regulate the Self-Renewal and Differentiation of Spinal Cord Neural Precursor Cells

Sanchez-Petidier¹,

Guerri²,

Moreno‐Manzano³

2021

Preprint

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Background: Toll-Like Receptors (TLRs) represent critical effectors in the host defense response against various pathogens; however, their known function during development has also highlighted a potential role in cell fate determination and neural differentiation. While glial cells and neural precursor cells (NPCs) of the spinal cord express both TLR2 and TLR4, their influence on self-renewal and cell differentiation remains incompletely described. Methods: TLR2, TLR4 knock-out and the wild type mice were employed for spinal cord tissue analysis and NPCs isolation at early post-natal stage. Sox2, FoxJ1 and Ki67 expression among others served to identify the undifferentiated and proliferative NPCs; GFAP, Olig2 and b-III-tubulin markers served to identify astrocytes, oligodendrocytes and neurons respectively after NPC spontaneous differentiation. Multiple comparisons were analyzed using one-way ANOVA, with appropriate corrections such as Tukey's post hoc tests used for comparisons. Results: We discovered that the deletion of TLR2 or TLR4 significantly reduced the number of Sox2-expressing NPCs in the neonatal mouse spinal cord. While TLR2-knockout NPCs displayed enhanced self-renewal, increased proliferation and apoptosis, and delayed neural differentiation, the absence of TLR4 promoted the neural differentiation of NPCs without affecting proliferation, producing long projecting neurons. TLR4 knock-out NPCs showed significantly higher expression of Neurogenin1, that would be involved in the activation of this neurogenic program by a ligand and microenvironment-independent mechanism. Interestingly, the absence of both TLR2 and TLR4 in NPCs impeded oligodendrocyte precursor cell maturation to a similar degree. Conclusions: Our data suggest that Toll-Like receptors are needed to maintain Sox2 positive neural progenitors in the spinal cord, however possess distinct regulatory roles in mouse neonatal spinal cord NPCs - while TLR2 and TLR4 play a similar role in oligodendrocytic differentiation, they differentially influence neural differentiation.

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Toll-like receptors 4, 5, 6 and 7 are constitutively expressed in non-human primate retinal neurons

Cited by 10 publications

References 56 publications

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Toll-like receptors 2 and 4 differentially regulate the self-renewal and differentiation of spinal cord neural precursor cells

Toll-Like Receptors 2 and 4 Differentially Regulate the Self-Renewal and Differentiation of Spinal Cord Neural Precursor Cells

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