Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms

Acıoğlu, Çiğdem; Mirabelli, Ersilia; Baykal, Ahmet Tarık; Ni, Li; Ratnayake, Ayomi; Heary, Robert F.; Elkabes, Stella

doi:10.1016/j.bbi.2016.03.027

Cited by 31 publications

(24 citation statements)

References 102 publications

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“…We have shown that a TLR9 antagonist, oligodeoxynucleotide 2088 (ODN 2088), alleviates functional deficits and improves histopathology in mice sustaining an SCI [28,29]. We also reported that TLR9 immunoreactivity and mRNA are found in astrocytes, in vitro [15] and in vivo [30]. Direct inhibition of TLR9 in pure spinal cord (SC) astrocyte cultures alters the release of cytokines and chemokines [15] raising the possibility that astroglial TLR9 antagonism could modulate astrocyte-to-macrophage signals and this, in turn, could alter astrocyte-induced chemotaxis and polarization of macrophages.…”

Section: Introductionmentioning

confidence: 99%

“…Astrocytes play many fundamental roles in health and disease, including maintenance of homeostasis [11], modulation of neuronal and synaptic function [12], repair of the blood-brain barrier [13], and protection of neurons from insults [14]. Astrocytes express toll-like receptors (TLRs) [15][16][17], which are pattern recognition receptors (PRRs) that are best known for their role in the innate immune system in response to infections. TLRs are the first sensors of danger and recognize conserved molecular motifs in pathogens collectively called pathogen-associated molecular patterns (PAMPs).…”

Section: Introductionmentioning

confidence: 99%

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Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury

Heary

et al. 2020

J Neuroinflammation

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Background: The recruitment of immune system cells into the central nervous system (CNS) has a profound effect on the outcomes of injury and disease. Glia-derived chemoattractants, including chemokines, play a pivotal role in this process. In addition, cytokines and chemokines influence the phenotype of infiltrating immune cells. Depending on the stimuli present in the local milieu, infiltrating macrophages acquire the classically activated M1 or alternatively activated M2 phenotypes. The polarization of macrophages into detrimental M1 versus beneficial M2 phenotypes significantly influences CNS pathophysiology. Earlier studies indicated that a toll-like receptor 9 (TLR9) antagonist modulates astrocytederived cytokine and chemokine release. However, it is not known whether these molecular changes affect astrocyteinduced chemotaxis and polarization of macrophages. The present studies were undertaken to address these issues. Methods: The chemotaxis and polarization of mouse peritoneal macrophages by spinal cord astrocytes were evaluated in a Transwell co-culture system. Arrays and ELISA were utilized to quantify chemokines in the conditioned medium (CM) of pure astrocyte cultures. Immunostaining for M1-and M2-specific markers characterized the macrophage phenotype. The percentage of M2 macrophages at the glial scar was determined by stereological approaches in mice sustaining a mid-thoracic spinal cord contusion injury (SCI) and intrathecally treated with oligodeoxynucleotide 2088 (ODN 2088), the TLR9 antagonist. Statistical analyses used two-tailed independent-sample t-test and one-way analysis of variance (ANOVA) followed by Tukey's post hoc test. A p value < 0.05 was considered to be statistically significant. Results: ODN 2088-treated astrocytes significantly increased the chemotaxis of peritoneal macrophages via release of chemokine (C-C motif) ligand 1 (CCL1). Vehicle-treated astrocytes polarized macrophages into the M2 phenotype and ODN 2088-treated astrocytes promoted further M2 polarization. Reduced CCL2 and CCL9 release by astrocytes in response to ODN 2088 facilitated the acquisition of the M2 phenotype, suggesting that CCL2 and CCL9 are negative regulators of M2 polarization. The percentage of M2 macrophages at the glial scar was higher in mice sustaining a SCI and receiving ODN 2088 treatment as compared to vehicle-treated injured controls. Conclusions: TLR9 antagonism could create a favorable environment during SCI by supporting M2 macrophage polarization and chemotaxis via modulation of astrocyte-to-macrophage signals.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury

Heary

et al. 2020

J Neuroinflammation

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“…As the defender of CNS, astrocytes play an important role in the protection of CNS [18,19]. Impairment of astrocytes could injure water and metabolic support, transmitter uptake in CNS cells, thereby influencing neuronal survival [20,21].…”

Section: Discussionmentioning

confidence: 99%

Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

Zhang

Wang²,

Ren

et al. 2016

IJMS

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Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes. Furthermore, glutamate activated Ca2+ release, thereby inducing endoplasmic reticulum (ER) stress in astrocytes, while morphine attenuated this deleterious effect. Using siRNA to reduce the expression of κ-opioid receptor, morphine could not effectively inhibit glutamate-stimulated Ca2+ release in astrocytes, the protective effect of morphine on glutamate-injured astrocytes was also suppressed. These results suggested that morphine could protect astrocytes from glutamate-induced apoptosis via reducing Ca2+ overload and ER stress pathways. In conclusion, this study indicated that excitotoxicity participated in the glutamate mediated apoptosis in astrocytes, while morphine attenuated this deleterious effect via regulating Ca2+ release and ER stress.

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“…Microglial and other myeloid lineage cells express innate immune response-related receptors [14][15][16]. Antigen recognition in innate immune response is mediated by pattern recognition receptors, such as NOD-Like Receptor Family Receptors (NLRs), which recognize Pathogen-Associated Molecular Patterns (PAMPs) and Danger-Associated Molecular Patterns (DAMPs) [17].…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

Microglial NLRP3 Activity in Alzheimer's Disease

Oliveira¹

2017

Int J Brain Disord Treat

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Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms

Cited by 31 publications

References 102 publications

Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury

Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury

Morphine Protects Spinal Cord Astrocytes from Glutamate-Induced Apoptosis via Reducing Endoplasmic Reticulum Stress

Microglial NLRP3 Activity in Alzheimer's Disease

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