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Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages.

Shin T, Ahn M, Matsumoto Y - Anat Cell Biol (2012)

Bottom Line: EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein.EAE is mediated by CD4(+) Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells.This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Anatomy, Veterinary Medical Research Institute, College of Veterinary Medicine, Jeju National University, Jeju, Korea. ; Functional and Systems Neurobiology, Cajal Institute, Madrid, Spain.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic paralytic central nervous system disease, in which most rats spontaneously recover from paralysis. EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein. EAE is mediated by CD4(+) Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells. Recently, it was established that classically activated macrophages (M1 phenotype) play an important role in the initiation of EAE, while alternatively activated macrophages (M2 phenotype) contribute to spontaneous recovery from rat EAE. This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of the relationship between clinical signs and inflammatory cells and their products in active monophasic experimental autoimmune encephalomyelitis. Clinical signs largely match the patterns of inflammatory molecules. iNOS, inducible nitric oxide synthase; NK, natural killer; T-reg, regulatory T cell.
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Figure 2: Schematic diagram of the relationship between clinical signs and inflammatory cells and their products in active monophasic experimental autoimmune encephalomyelitis. Clinical signs largely match the patterns of inflammatory molecules. iNOS, inducible nitric oxide synthase; NK, natural killer; T-reg, regulatory T cell.

Mentions: The relationship between iNOS and arginase-1, a competitive enzyme for iNOS, will be further discussed (Fig. 2). Upon activation in EAE, macrophages in the lesions are immunopositive for iNOS, which generates nitric oxide through L-arginine. Physiological levels of nitric oxide are beneficial, but can be transiently harmful in rat EAE, when autoimmune T cells infiltrate at the time of EAE induction [71]. However, nitric oxide is also regarded as an EAE-resistant molecule [6, 72], suggesting that the timing of inhibition of iNOS is associated with disease suppression. It is believed that iNOS activity is quickly exhausted in macrophages once activated. Arginase, a competitive enzyme of iNOS, then substitutes for the catalysis of L-arginine, resulting in less production of nitric oxide in the CNS, during recovery-stage EAE [11]. Since some macrophages express both iNOS and arginase, and the expression of iNOS in macrophages is inversely related to that of arginase, it is possible that the phenotypic changes from hematogenous M1 macrophages to M2 macrophages may occur within the same cell in rat EAE. However, it remains possible that phenotypically differentiated M2 macrophages infiltrated alongside hematogenous M1 macrophages. Another possibility is that M2 macrophages originated from proliferation of microglial cells, because microglia were shown to proliferate in rat EAE [14, 58], and alternative activation of microglial cells occurred via IL-4 in a mouse EAE model [73]. A similar result was found in a rat spinal cord injury model in which the majority of macrophages were found to be proliferating [74]. An inverse relationship between iNOS and arginase [75] was identified in a model of spinal cord injury in rats. Taken together, data from the two models of spinal cord inflammation suggest that M2 macrophages may originate from either hematogenous monocytes (via phenotypic differentiation) or activated microglial cells. Both sources of M2 macrophages have been associated with modulation of EAE through the secretion of immunomodulatory molecules, including activin A, in the rat active model. The neuroprotective capacity of macrophages in rat EAE lesions represents a distinct story, but is also beneficial for remission of rat EAE.


Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages.

Shin T, Ahn M, Matsumoto Y - Anat Cell Biol (2012)

Schematic diagram of the relationship between clinical signs and inflammatory cells and their products in active monophasic experimental autoimmune encephalomyelitis. Clinical signs largely match the patterns of inflammatory molecules. iNOS, inducible nitric oxide synthase; NK, natural killer; T-reg, regulatory T cell.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472139&req=5

Figure 2: Schematic diagram of the relationship between clinical signs and inflammatory cells and their products in active monophasic experimental autoimmune encephalomyelitis. Clinical signs largely match the patterns of inflammatory molecules. iNOS, inducible nitric oxide synthase; NK, natural killer; T-reg, regulatory T cell.
Mentions: The relationship between iNOS and arginase-1, a competitive enzyme for iNOS, will be further discussed (Fig. 2). Upon activation in EAE, macrophages in the lesions are immunopositive for iNOS, which generates nitric oxide through L-arginine. Physiological levels of nitric oxide are beneficial, but can be transiently harmful in rat EAE, when autoimmune T cells infiltrate at the time of EAE induction [71]. However, nitric oxide is also regarded as an EAE-resistant molecule [6, 72], suggesting that the timing of inhibition of iNOS is associated with disease suppression. It is believed that iNOS activity is quickly exhausted in macrophages once activated. Arginase, a competitive enzyme of iNOS, then substitutes for the catalysis of L-arginine, resulting in less production of nitric oxide in the CNS, during recovery-stage EAE [11]. Since some macrophages express both iNOS and arginase, and the expression of iNOS in macrophages is inversely related to that of arginase, it is possible that the phenotypic changes from hematogenous M1 macrophages to M2 macrophages may occur within the same cell in rat EAE. However, it remains possible that phenotypically differentiated M2 macrophages infiltrated alongside hematogenous M1 macrophages. Another possibility is that M2 macrophages originated from proliferation of microglial cells, because microglia were shown to proliferate in rat EAE [14, 58], and alternative activation of microglial cells occurred via IL-4 in a mouse EAE model [73]. A similar result was found in a rat spinal cord injury model in which the majority of macrophages were found to be proliferating [74]. An inverse relationship between iNOS and arginase [75] was identified in a model of spinal cord injury in rats. Taken together, data from the two models of spinal cord inflammation suggest that M2 macrophages may originate from either hematogenous monocytes (via phenotypic differentiation) or activated microglial cells. Both sources of M2 macrophages have been associated with modulation of EAE through the secretion of immunomodulatory molecules, including activin A, in the rat active model. The neuroprotective capacity of macrophages in rat EAE lesions represents a distinct story, but is also beneficial for remission of rat EAE.

Bottom Line: EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein.EAE is mediated by CD4(+) Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells.This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Anatomy, Veterinary Medical Research Institute, College of Veterinary Medicine, Jeju National University, Jeju, Korea. ; Functional and Systems Neurobiology, Cajal Institute, Madrid, Spain.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic paralytic central nervous system disease, in which most rats spontaneously recover from paralysis. EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein. EAE is mediated by CD4(+) Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells. Recently, it was established that classically activated macrophages (M1 phenotype) play an important role in the initiation of EAE, while alternatively activated macrophages (M2 phenotype) contribute to spontaneous recovery from rat EAE. This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages.

No MeSH data available.


Related in: MedlinePlus