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

Abstract

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.

KDM6B Negatively Regulates the Neurogenesis Potential of Apical Papilla Stem Cells via HES1

“…Its expression is also upregulated in neural progenitor cells during neurogenesis. The expression of Nestin and β-III Tubulin serves as a useful indicator of the potential for neural regeneration after a spinal cord injury [ 27 , 28 ]. The upregulation of the expression of Neurod, TH, and β-III Tubulin was also observed after KDM6B knockdown, suggesting that SCAPs were inclined to differentiate into neuron-like cells during induction.…”

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

“…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 ).…”

“…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 ).…”

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…The glia represents the biggest population of cells in the human brain, with 10 times more cells than the neurons [ 36 , 37 ]. These cells perform several pivotal functions such as energetic support for neurons [ 38 , 39 , 40 ], the formation of the blood–brain barrier (BBB) [ 41 , 42 ], the regulation of neurotransmitters [ 43 , 44 , 45 ], the development and remodeling of synapses [ 46 , 47 , 48 ], detoxification [ 49 , 50 , 51 ], the control of the fluid/electrolyte homeostasis [ 52 ], the control of metabolism [ 53 , 54 ], neuroendocrine function [ 55 ], innate immunity response [ 56 , 57 ], and myelination [ 58 , 59 ]. These functions confer on them a key role in maintaining homeostasis, the disruption of which can lead to neuropsychiatric and neurodegenerative diseases [ 59 , 60 , 61 , 62 , 63 , 64 ].…”

“…In addition to axonal myelination, OLs control extracellular potassium concentration and, as mentioned above, provide metabolic and trophic supply to myelin, secrete glial and brain-derived neurotrophic factors (GDNF and BDNF), and modulate the axonal growth [ 117 , 122 , 123 ], all of which highlight their importance in the functioning of CNS. Like microglia and astrocytes, OLs also express TLRs, which are considered of significant importance in myelin formation [ 58 , 124 , 125 ]. Importantly and of direct relevance to our discussion, the dysregulation of these glial cells, which contain nAChRs, can contribute to the pathogenesis of PD [ 121 ].…”