Serum pro‐inflammatory and anti‐inflammatory cytokines and the pathogenesis of experimental autoimmune encephalomyelitis

Jahan-Abad, Ali Jahanbazi; Karima, Saeed; Shateri, Somayeh; Baram, Somayeh Mahmoodi; Rajaei, Shima; Morteza-Zadeh, Parastoo; Borhani-Haghighi, Maryam; Salari, Ali-Akbar; Nikzamir, Abdolrahim; Gorji, Ali

doi:10.1111/neup.12612

Cited by 26 publications

(23 citation statements)

References 46 publications

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“…Proinflammatory cytokines also increase blood vessel permeability resulting in an influx of inflammatory cells including auto-reactive T cells and monocytes resulting in more inflammation, demyelination and tissue damage [29,48,49]. Downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines results in amelioration of MS/EAE disease progression [50,51]. Prior studies also Fig.…”

Section: Discussionmentioning

confidence: 97%

Amnion-Derived Multipotent Progenitor Cells Suppress Experimental Optic Neuritis and Myelitis

et al. 2021

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The human amnion has been used for decades in wound healing, particularly burns. Amnion epithelial cells (AECs) have been the focus of extensive research based on their possible pluripotent differentiation ability. A novel, cultured cell population derived from AECs, termed human amnion-derived multipotent progenitor (AMP) cells, secrete numerous cytokines and growth factors that enhance tissue regeneration and reduce inflammation. This AMP cell secretome, termed ST266, is a unique biological solution that accumulates in eyes and optic nerves following intranasal delivery, resulting in selective suppression of optic neuritis in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, but not myelitis at the administered dose. We tested the hypothesis that systemic AMP cell administration could suppress both optic neuritis and myelitis in EAE. Intravenous and intraperitoneal administration of AMP cells significantly reduced ascending paralysis and attenuated visual dysfunction in EAE mice. AMP cell treatment increased retinal ganglion cell (RGC) survival and decreased optic nerve inflammation, with variable improvement in optic nerve demyelination and spinal cord inflammation and demyelination. Results show systemic AMP cell administration inhibits RGC loss and visual dysfunction similar to previously demonstrated effects of intranasally delivered ST266. Importantly, AMP cells also promote neuroprotective effects in EAE spinal cords, marked by reduced paralysis. Protective effects of systemically administered AMP cells suggest they may serve as a potential novel treatment for multiple sclerosis.

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Section: Discussionmentioning

confidence: 97%

Amnion-Derived Multipotent Progenitor Cells Suppress Experimental Optic Neuritis and Myelitis

et al. 2021

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“…Taking advantage of the blood sampling, we analyzed the concentration of pro- and anti-inflammatory cytokines in the serum of both animal groups, using a bead-based immunoassay. Specifically, we measured the levels of innate and adaptive immune cytokines such as IL-2, IL-6, IL-17, IL-22, IFNγ and TNFα, all associated with EAE pathology 32 . Microglial ablation did not lead to any difference in the cytokine profiles in the serum at EAE pre-onset (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Neurological score was assessed daily and ranged from 0 to 8 as previously described 23 . Depending on the experiment, mice were euthanized at different phases of the model, which are defined as pre-onset (prior to the appearance of the first symptoms; day post-immunization (dpi) 8-9), onset (mice show first symptomatology; dpi 10-14) and chronic phase (mice have stabilized neurological score, dpi [30][31][32][33][34][35].…”

Section: Eae Inductionmentioning

confidence: 99%

Microglia and meningeal macrophages depletion delay the onset of experimental autoimmune encephalomyelitis

Montilla

Zabala

Er-Lukowiak

et al. 2022

Preprint

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In multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, both resident microglia and infiltrating macrophages contribute to demyelination as well as spontaneous remyelination. Nevertheless, the specific roles of microglia versus macrophages are unknown. We investigated the influence of microglia in EAE using the colony stimulating factor 1 receptor (CSF-1R) inhibitor, PLX5622, to deplete microglial population and Ccr2RFP/+fmsEGFP/+ mice, to distinguish peripheral macrophages and microglia. PLX5622 treatment depleted microglia and meningeal macrophages, and provoked a massive infiltration of CCR2+ macrophages into demyelinating lesions and spinal cord parenchyma. PLX5622 treatment did not alter EAE chronic phase. In contrast, microglia and meningeal macrophages depletion reduced the expression of CD80 co-stimulatory molecule in dendritic and myeloid cells and reduced T cell reactivation and proliferation in the spinal cord parenchyma, inducing a significant delay in EAE onset. Altogether, these data points to a specific role of CNS microglia meningeal macrophages in antigen presentation and T cell reactivation at initial stages of the EAE model.

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“…IL-6 has been hypothesized to play a crucial role in the induction phase of EAE based on research showing that IL-6-deficient mice immunized with MOG developed milder EAE and at a significantly lower frequency when compared with wild-type mice; however, those injected with IL-6 before the onset of motor dysfunction showed a significantly delayed onset, but developed severe EAE at a high frequency [ 49 ]. In addition, the serum concentrations of Th1 and Th17 cytokines, IL-6, IL-1β, IL-1α, and prostaglandin E2 in EAE mice were significantly higher than those observed in control mice [ 50 ]. Furthermore, a statistically significant positive correlation was found between the IL-6/IL-10 ratio and EAE severity, demyelination rate, and lymphocyte infiltration in EAE mice [ 50 ].…”

Section: Role Of Il-6 In Neuropathic Pain Of Experimental Autoimmune Encephalomyelitismentioning

confidence: 99%

“…In addition, the serum concentrations of Th1 and Th17 cytokines, IL-6, IL-1β, IL-1α, and prostaglandin E2 in EAE mice were significantly higher than those observed in control mice [ 50 ]. Furthermore, a statistically significant positive correlation was found between the IL-6/IL-10 ratio and EAE severity, demyelination rate, and lymphocyte infiltration in EAE mice [ 50 ]. In addition, nuclear factor kappa B triggers a positive feedback loop for IL-6 expression (IL-6 amplifier) in endothelial cells, and its activation can lead to excess expression of various chemokines and cytokines including CCL20 and IL-6 and the development of autoimmune diseases such as EAE [ 51 ].…”

Section: Role Of Il-6 In Neuropathic Pain Of Experimental Autoimmune Encephalomyelitismentioning

confidence: 99%

Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders

Serizawa¹,

Tomizawa-Shinohara²,

Miyake³

et al. 2021

Inflamm Regener

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Background Neuropathic pain in neuroimmunological disorders refers to pain caused by a lesion or disease of the somatosensory system such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS and NMOSD are autoimmune disorders of the central nervous system, and ≥ 50% of patients with these disorders experience chronic neuropathic pain. The currently available medications for the management of neuropathic pain have limited effectiveness in patients with MS and NMOSD, and there is an unmet medical need to identify novel therapies for the management of chronic neuropathic pain in these patients. In this review article, we summarize the role of interleukin-6 (IL-6) in the pathogenesis of MS and NMOSD and the ameliorative effects of anti–IL-6 therapies in mouse models of experimental autoimmune encephalomyelitis (EAE). Main body Intraperitoneal injection of MR16-1, an anti–IL-6 receptor (IL-6R) antibody, reduced mechanical allodynia and spontaneous pain in EAE mice, which was attributed to a reduction in microglial activation and inhibition of the descending pain inhibitory system. The effect of anti–IL-6 therapies in ameliorating neuropathic pain in the clinical setting is controversial; a reduction in pain intensity has been reported with an anti–IL-6 antibody in four studies, namely a case report, a pilot study, a retrospective observational study, and a case series. Pain intensity was evaluated using a numerical rating scale (NRS), with a lower score indicating lesser pain. A reduction in the NRS score was reported in all four studies. However, in two randomized controlled trials of another anti–IL-6R antibody, the change in the visual analog scale pain score was not statistically significantly different when compared with placebo. This was attributed to the low mean pain score at baseline in both the trials and the concomitant use of medications for pain in one of the trials, which may have masked the effects of the anti–IL-6R antibody on neuropathic pain. Conclusion Thus, anti–IL-6 therapies might have a potential to reduce neuropathic pain, but further investigations are warranted to clarify the effect of inhibition of IL-6 signaling on neuropathic pain associated with MS and NMOSD.

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Serum pro‐inflammatory and anti‐inflammatory cytokines and the pathogenesis of experimental autoimmune encephalomyelitis

Cited by 26 publications

References 46 publications

Amnion-Derived Multipotent Progenitor Cells Suppress Experimental Optic Neuritis and Myelitis

Amnion-Derived Multipotent Progenitor Cells Suppress Experimental Optic Neuritis and Myelitis

Microglia and meningeal macrophages depletion delay the onset of experimental autoimmune encephalomyelitis

Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders

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