Distribution of Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-α in the Peripheral Nervous System of Lewis Rats during Ascending Paresis and Spontaneous Recovery from Experimental Autoimmune Neuritis

Hoz, Cristiane Lucia Rodriguez de la; Castro, Fabiano R.; Santos, Leonilda Maria Barbosa dos; Langone, Francesco

doi:10.1159/000243086

Cited by 12 publications

(4 citation statements)

References 78 publications

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“…Macrophages, the major cell population in the inflamed peripheral nerves of EAN, directly participated the local inflammation by phagocytic attack and secretion of pro-inflammatory mediators like NO, matrix metalloproteinases (MMPs), and TNF-α. According to previous report, the amount of cells bearing inducible nitric oxide synthase (iNOS) and TNF-α was parallel to the clinical symptoms of EAN [ 34 ]. In response to inflammatory stimuli, iNOS produces amounts of nitric oxide (NO), which is considered as a key process in the demyelination in both peripheral and central nervous system [ 35 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

Enhanced glycolysis contributes to the pathogenesis of experimental autoimmune neuritis

Liu

Zhang

Yang

et al. 2018

J Neuroinflammation

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BackgroundWith the recognition of the key roles of cellular metabolism in immunity, targeting metabolic pathway becomes a new strategy for autoimmune disease treatment. Guillain-Barré syndrome (GBS) is an acute immune-mediated inflammatory demyelinating disease of the peripheral nervous system, characterized by inflammatory cell infiltration. These inflammatory cells, including activated macrophages, Th1 cells, and Th17 cells, generally undergo metabolic reprogramming and rely mainly on glycolysis to exert functions. This study aimed to explore whether enhanced glycolysis contributed to the pathogenesis of experimental autoimmune neuritis (EAN), a classic model of GBS.MethodsPreventive and therapeutic treatments with glycolysis inhibitor, 2-deoxy-d-glucose (2-DG), were applied to EAN rats. The effects of treatments were determined by clinical scoring, weighting, and tissue examination. Flow cytometry and ELISA were used to evaluate T cell differentiation, autoantibody level, and macrophage functions in vivo and in vitro.ResultsGlycolysis inhibition with 2-DG not only inhibited the initiation, but also prevented the progression of EAN, evidenced by the improved clinical scores, weight loss, inflammatory cell infiltration, and demyelination of sciatic nerves. 2-DG inhibited the differentiation of Th1, Th17, and Tfh cells but enhanced Treg cell development, accompanied with reduced autoantibody secretion. Further experiments in vitro proved glycolysis inhibition decreased the nitric oxide production and phagocytosis of macrophages and suppressed the maturation of dendritic cells (DC).ConclusionThe effects of glycolysis inhibition on both innate and adaptive immune responses and the alleviation of animal clinical symptoms indicated that enhanced glycolysis contributed to the pathogenesis of EAN. Glycolysis inhibition may be a new therapy for GBS.

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Section: Discussionmentioning

confidence: 99%

Enhanced glycolysis contributes to the pathogenesis of experimental autoimmune neuritis

Liu

Zhang

Yang

et al. 2018

J Neuroinflammation

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“…The MMPs facilitate the migration of inflammatory cells and the demyelination in the PNS [ 50 , 51 ]. NO is produced by inducible nitric oxide synthase (iNOS) in macrophages under the simulation by IFN- γ and TNF- α and related to nerve demyelination in the peripheral neuropathies [ 52 ]. Therefore, a complex network of cytokines, chemokines, adhesion molecules, NO, and MMPs is mediated by macrophages in GBS.…”

Section: Effector Functions Of Macrophages In Gbs and Eanmentioning

confidence: 99%

Beneficial or Harmful Role of Macrophages in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis

Shen

Chu

Lang

et al. 2018

Mediators of Inflammation

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Guillain-Barré syndrome (GBS), an immune-mediated demyelinating peripheral neuropathy, is characterized by acute weakness of the extremities and areflexia or hyporeflexia. Experimental autoimmune neuritis (EAN) is a common animal model for GBS, which represents a CD4+ T cell-mediated inflammatory autoimmune demyelination of the peripheral nervous system (PNS), and is used to investigate the pathogenic mechanism of GBS. It has been found that macrophages play a critical role in the pathogenesis of both GBS and EAN. Macrophages have been primarily classified into two major phenotypes: proinflammatory macrophages (M1) and anti-inflammatory macrophages (M2). The two different macrophage subsets M1 and M2 may play a decisive role in initiation and development of GBS and EAN. However, recently, it has been indicated that the roles of macrophages in immune regulation and autoimmune diseases are more complex than those suggested by a simple M1-M2 dichotomy. Macrophages might exert either inflammatory or anti-inflammatory effect by secreting pro- or anti-inflammatory cytokines, and either inducing the activation of T cells to mediate immune response, resulting in inflammation and demyelination in the PNS, or promoting disease recovery. In this review, we summarize the dual roles of macrophages in GBS and EAN and explore the mechanism of macrophage polarization to provide a potential therapeutic approach for GBS in the future.

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“…How this might impact peripheral demyelinating disease has not been elucidated. However, in Guillain-Barr e syndrome, macrophages produce elevated levels of the M1 marker TNF-a, which when combined with direct phagocytosis of myelin, likely contributes the demyelination process (De La Hoz et al, 2010;Shin et al, 2013).…”

Section: Increased Neuronal Activity Favorably Alters the Immune Micrmentioning

confidence: 99%

Dynamic impact of brief electrical nerve stimulation on the neural immune axis—polarization of macrophages toward a pro‐repair phenotype in demyelinated peripheral nerve

McLean

Verge

2016

Glia

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Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro-inflammatory M1 to pro-repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro-repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro-inflammatory/M1 toward a predominantly pro-repair/M2 one, as evidenced by an increased incidence of expression of M2-associated phenotypic markers in identified macrophages and a decrease in M1-associated marker expression. This was discernible at 3 days post-ES (8 days post-LPC) and continued at the 5 day post-ES (10 days post-LPC) time point examined. ES also affected chemokine (C-C motif) ligand 2 (CCL2; aka MCP-1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro-repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016;64:1546-1561.

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Distribution of Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-α in the Peripheral Nervous System of Lewis Rats during Ascending Paresis and Spontaneous Recovery from Experimental Autoimmune Neuritis

Cited by 12 publications

References 78 publications

Enhanced glycolysis contributes to the pathogenesis of experimental autoimmune neuritis

Enhanced glycolysis contributes to the pathogenesis of experimental autoimmune neuritis

Beneficial or Harmful Role of Macrophages in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis

Dynamic impact of brief electrical nerve stimulation on the neural immune axis—polarization of macrophages toward a pro‐repair phenotype in demyelinated peripheral nerve

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