Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+ T cells in aged rats

Stojić-Vukanić, Zorica; Nacka-Aleksić, Mirjana; Pilipović, Ivan; Vujnović, Ivana; Blagojević, Veljko; Kosec, Duško; Dimitrijević, Mirjana; Leposavić, Gordana

doi:10.1186/s12979-015-0044-x

Cited by 13 publications

(14 citation statements)

References 64 publications

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“…As previously shown [28,39], although minimal single cell infiltrate is regularly seen (independently on immunization protocol) in SC of young AO rats [39], they did not develop neurological signs of EAE. On the contrary, DA rats developed clinically manifested disease.…”

Section: Resultssupporting

confidence: 73%

“…To purify CD4+ T cells from mononuclear SC and dLN cell suspensions a two-step magnetic-activated cell sorting (MACS) procedure, using the equipment and reagents supplied by Miltenyi Biotec (Gladbach, Germany), was applied [28]. The cells were labeled using rat CD8a microbeads and loaded onto LS column, placed in the magnetic field of the Quadro MACS separator, for negative selection.…”

Section: Methodsmentioning

confidence: 99%

“…Target mRNA levels were quantified by the 2 -ΔΔCt method with SDS v1.4.0. software (Applied Biosystems), using β-actin as a normalizer, as it has been previously suggested [28,41]. …”

Section: Methodsmentioning

confidence: 99%

“…However, it has been shown that the pathogenicity of autoreactive Th17 cells in mice and, possibly in rats is linked with their production of GM-CSF [17,18,27]. Given that Th17 lymphocyte response is promoted in CFA-induced models of autoimmunity [12], and that more severe EAE in the rat is associated with higher frequency of Th17 cells co-producing IFN-γ and IL-17 in spinal cord (SC) [27,28], multi-cytokine producing Th17 lymphocytes are worthy of special attention in studies of rat susceptibility to EAE.…”

Section: Introductionmentioning

confidence: 99%

“…We chose AO rats considering that the increase in their sensitivity to EAE induction with aging coincides with the increase in encephalitogenic GM-CSF+ Th-cell generation in dLNs/SC and higher frequency of GM-CSF+ Th cells infiltrating the SC [28]. …”

Section: Introductionmentioning

confidence: 99%

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GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

et al. 2016

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Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+IFN-γ+, IL-17+IFN-γ-, and IL-17-IFN-γ+ cells accompanied by higher frequency of IL-17-IFN-γ- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+IFN-γ+ Th17 cells in SC) on GM-CSF+IFN-γ+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+IFN-γ+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1β, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45hi cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto)reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE.

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Section: Resultssupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

“…Target mRNA levels were quantified by the 2 -ΔΔCt method with SDS v1.4.0. software (Applied Biosystems), using β-actin as a normalizer, as it has been previously suggested [28,41]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

et al. 2016

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β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males

et al. 2022

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Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimorphism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β 2 -adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte trafficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them.

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Noradrenaline modulates CD4+ T cell priming in rat experimental autoimmune encephalomyelitis: a role for the α1-adrenoceptor

et al. 2019

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Aging diminishes the resistance of AO rats to EAE: putative role of enhanced generation of GM-CSF Expressing CD4+ T cells in aged rats

Cited by 13 publications

References 64 publications

GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males

Noradrenaline modulates CD4+ T cell priming in rat experimental autoimmune encephalomyelitis: a role for the α1-adrenoceptor

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