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Ubiquitous Over-Expression of Chromatin Remodeling Factor SRG3 Ameliorates the T Cell-Mediated Exacerbation of EAE by Modulating the Phenotypes of both Dendritic Cells and Macrophages.

Lee SW, Park HJ, Jeon SH, Lee C, Seong RH, Park SH, Hong S - PLoS ONE (2015)

Bottom Line: We found that the outcome of EAE development was completely different depending on the expression pattern of SRG3.SRG3 over-expression not only reduced pro-inflammatory cytokine production by DCs but also shifted macrophages from the inducible nitric oxide synthase (iNOS)-expressing M1 phenotype to the arginase-1-expressing M2 phenotype during EAE.Taken together, our results provide the first evidence supporting the development of a new therapeutic strategy for EAE involving the modulation of SRG3 expression to induce M2 and Th2 polarization, thereby inhibiting inflammatory immune responses.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul 143-747, Korea; School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.

ABSTRACT
Although SWI3-related gene (SRG3), a chromatin remodeling factor, is critical for various biological processes including early embryogenesis and thymocyte development, it is unclear whether SRG3 is involved in the differentiation of CD4+ T cells, the key mediator of adaptive immune responses. Because it is known that experimental autoimmune encephalomyelitis (EAE) development is determined by the activation of CD4+ T helper cells, here, we investigated the role of SRG3 in EAE development using SRG3 transgenic mouse models exhibiting two distinct SRG3 expression patterns: SRG3 expression driven by either the CD2 or β-actin promoter. We found that the outcome of EAE development was completely different depending on the expression pattern of SRG3. The specific over-expression of SRG3 using the CD2 promoter facilitated EAE via the induction of Th1 and Th17 cells, whereas the ubiquitous over-expression of SRG3 using the β-actin promoter inhibited EAE by promoting Th2 differentiation and suppressing Th1 and Th17 differentiation. In addition, the ubiquitous over-expression of SRG3 polarized CD4+ T cell differentiation towards the Th2 phenotype by converting dendritic cells (DCs) or macrophages to Th2 types. SRG3 over-expression not only reduced pro-inflammatory cytokine production by DCs but also shifted macrophages from the inducible nitric oxide synthase (iNOS)-expressing M1 phenotype to the arginase-1-expressing M2 phenotype during EAE. In addition, Th2 differentiation in β-actin-SRG3 Tg mice during EAE was associated with an increase in the basophil and mast cell populations and in IL4 production. Furthermore, the increased frequency of Treg cells in the spinal cord of β-actin-SRG3 Tg mice might induce the suppression of and accelerate the recovery from EAE symptoms. Taken together, our results provide the first evidence supporting the development of a new therapeutic strategy for EAE involving the modulation of SRG3 expression to induce M2 and Th2 polarization, thereby inhibiting inflammatory immune responses.

No MeSH data available.


Related in: MedlinePlus

Differential outcome of EAE pathogenesis depending on the SRG3 over-expression pattern in MBP-specific TCR transgenic B10.PL mice: the development of EAE was suppressed in β-actin-SRG3 Tg mice but was facilitated in CD2-SRG3 Tg mice.(A-B) Both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice (upper panel) or both MBP TCR Tg B10.PL mice and β-acin-SRG3/MBP TCR double Tg B10.PL mice (lower panel) were either non-immunized or s.c. immunized with the MBP-Ac1-11 peptide in CFA. (A) Subsequently, the disease severity was monitored daily according to the classical EAE scoring system after immunization; one representative result out of two independent experiments is shown as the mean ± SD of 5 mice per group (*P<0.05, **P<0.01). (B) Spleens were prepared from the aforementioned four experimental groups, and corresponding photographs were captured (upper panel). Additionally, spleen weight (the middle panel) and total cell number (the lower panel) are shown as the mean values ± SD (n = 5; *P<0.05, **P<0.01).
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pone.0132329.g004: Differential outcome of EAE pathogenesis depending on the SRG3 over-expression pattern in MBP-specific TCR transgenic B10.PL mice: the development of EAE was suppressed in β-actin-SRG3 Tg mice but was facilitated in CD2-SRG3 Tg mice.(A-B) Both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice (upper panel) or both MBP TCR Tg B10.PL mice and β-acin-SRG3/MBP TCR double Tg B10.PL mice (lower panel) were either non-immunized or s.c. immunized with the MBP-Ac1-11 peptide in CFA. (A) Subsequently, the disease severity was monitored daily according to the classical EAE scoring system after immunization; one representative result out of two independent experiments is shown as the mean ± SD of 5 mice per group (*P<0.05, **P<0.01). (B) Spleens were prepared from the aforementioned four experimental groups, and corresponding photographs were captured (upper panel). Additionally, spleen weight (the middle panel) and total cell number (the lower panel) are shown as the mean values ± SD (n = 5; *P<0.05, **P<0.01).

Mentions: A previous study showed that SRG3 over-expression driven by the CD2 promoter facilitates MOG peptide-induced EAE development in B6 mice [7]. To confirm whether SRG3 over-expression accelerates the outcome of EAE in self-antigen-specific TCR Tg mice, which carry a more EAE-susceptible genetic background, we subjected MBP TCR transgenic (Tg) B10.PL mice (u haplotype) to MBP peptide-induced EAE. First, we examined whether CD2-SRG3 over-expression exacerbated EAE in MBP TCR Tg mice. As expected, CD2-SRG3/MBP TCR double Tg B10.PL mice developed EAE more severely and rapidly than MBP TCR single Tg mice (Fig 4A, upper panel). Because β-actin-SRG3 Tg mice are in the B6 (H2b) genetic background, next, these mice were backcrossed more than 7 times with MBP TCR Tg B10.PL (H2u) mice to generate β-actin-SRG3/MBP TCR double Tg mice carrying the H2u haplotype, which is well known to increase the susceptibility to EAE induction via MBP antigen immunization. Using these double Tg mice, we investigated whether distinct modes of SRG3 over-expression significantly influence the outcome of EAE upon MBP peptide immunization. Surprisingly, we found that the ubiquitous over-expression of SRG3 in β-actin-SRG3 Tg mice attenuated the severity and rate of EAE development compared to the endogenous expression of SRG3 in MBP TCR single Tg control mice (Fig 4A, lower panel).


Ubiquitous Over-Expression of Chromatin Remodeling Factor SRG3 Ameliorates the T Cell-Mediated Exacerbation of EAE by Modulating the Phenotypes of both Dendritic Cells and Macrophages.

Lee SW, Park HJ, Jeon SH, Lee C, Seong RH, Park SH, Hong S - PLoS ONE (2015)

Differential outcome of EAE pathogenesis depending on the SRG3 over-expression pattern in MBP-specific TCR transgenic B10.PL mice: the development of EAE was suppressed in β-actin-SRG3 Tg mice but was facilitated in CD2-SRG3 Tg mice.(A-B) Both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice (upper panel) or both MBP TCR Tg B10.PL mice and β-acin-SRG3/MBP TCR double Tg B10.PL mice (lower panel) were either non-immunized or s.c. immunized with the MBP-Ac1-11 peptide in CFA. (A) Subsequently, the disease severity was monitored daily according to the classical EAE scoring system after immunization; one representative result out of two independent experiments is shown as the mean ± SD of 5 mice per group (*P<0.05, **P<0.01). (B) Spleens were prepared from the aforementioned four experimental groups, and corresponding photographs were captured (upper panel). Additionally, spleen weight (the middle panel) and total cell number (the lower panel) are shown as the mean values ± SD (n = 5; *P<0.05, **P<0.01).
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Related In: Results  -  Collection

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pone.0132329.g004: Differential outcome of EAE pathogenesis depending on the SRG3 over-expression pattern in MBP-specific TCR transgenic B10.PL mice: the development of EAE was suppressed in β-actin-SRG3 Tg mice but was facilitated in CD2-SRG3 Tg mice.(A-B) Both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice (upper panel) or both MBP TCR Tg B10.PL mice and β-acin-SRG3/MBP TCR double Tg B10.PL mice (lower panel) were either non-immunized or s.c. immunized with the MBP-Ac1-11 peptide in CFA. (A) Subsequently, the disease severity was monitored daily according to the classical EAE scoring system after immunization; one representative result out of two independent experiments is shown as the mean ± SD of 5 mice per group (*P<0.05, **P<0.01). (B) Spleens were prepared from the aforementioned four experimental groups, and corresponding photographs were captured (upper panel). Additionally, spleen weight (the middle panel) and total cell number (the lower panel) are shown as the mean values ± SD (n = 5; *P<0.05, **P<0.01).
Mentions: A previous study showed that SRG3 over-expression driven by the CD2 promoter facilitates MOG peptide-induced EAE development in B6 mice [7]. To confirm whether SRG3 over-expression accelerates the outcome of EAE in self-antigen-specific TCR Tg mice, which carry a more EAE-susceptible genetic background, we subjected MBP TCR transgenic (Tg) B10.PL mice (u haplotype) to MBP peptide-induced EAE. First, we examined whether CD2-SRG3 over-expression exacerbated EAE in MBP TCR Tg mice. As expected, CD2-SRG3/MBP TCR double Tg B10.PL mice developed EAE more severely and rapidly than MBP TCR single Tg mice (Fig 4A, upper panel). Because β-actin-SRG3 Tg mice are in the B6 (H2b) genetic background, next, these mice were backcrossed more than 7 times with MBP TCR Tg B10.PL (H2u) mice to generate β-actin-SRG3/MBP TCR double Tg mice carrying the H2u haplotype, which is well known to increase the susceptibility to EAE induction via MBP antigen immunization. Using these double Tg mice, we investigated whether distinct modes of SRG3 over-expression significantly influence the outcome of EAE upon MBP peptide immunization. Surprisingly, we found that the ubiquitous over-expression of SRG3 in β-actin-SRG3 Tg mice attenuated the severity and rate of EAE development compared to the endogenous expression of SRG3 in MBP TCR single Tg control mice (Fig 4A, lower panel).

Bottom Line: We found that the outcome of EAE development was completely different depending on the expression pattern of SRG3.SRG3 over-expression not only reduced pro-inflammatory cytokine production by DCs but also shifted macrophages from the inducible nitric oxide synthase (iNOS)-expressing M1 phenotype to the arginase-1-expressing M2 phenotype during EAE.Taken together, our results provide the first evidence supporting the development of a new therapeutic strategy for EAE involving the modulation of SRG3 expression to induce M2 and Th2 polarization, thereby inhibiting inflammatory immune responses.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul 143-747, Korea; School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.

ABSTRACT
Although SWI3-related gene (SRG3), a chromatin remodeling factor, is critical for various biological processes including early embryogenesis and thymocyte development, it is unclear whether SRG3 is involved in the differentiation of CD4+ T cells, the key mediator of adaptive immune responses. Because it is known that experimental autoimmune encephalomyelitis (EAE) development is determined by the activation of CD4+ T helper cells, here, we investigated the role of SRG3 in EAE development using SRG3 transgenic mouse models exhibiting two distinct SRG3 expression patterns: SRG3 expression driven by either the CD2 or β-actin promoter. We found that the outcome of EAE development was completely different depending on the expression pattern of SRG3. The specific over-expression of SRG3 using the CD2 promoter facilitated EAE via the induction of Th1 and Th17 cells, whereas the ubiquitous over-expression of SRG3 using the β-actin promoter inhibited EAE by promoting Th2 differentiation and suppressing Th1 and Th17 differentiation. In addition, the ubiquitous over-expression of SRG3 polarized CD4+ T cell differentiation towards the Th2 phenotype by converting dendritic cells (DCs) or macrophages to Th2 types. SRG3 over-expression not only reduced pro-inflammatory cytokine production by DCs but also shifted macrophages from the inducible nitric oxide synthase (iNOS)-expressing M1 phenotype to the arginase-1-expressing M2 phenotype during EAE. In addition, Th2 differentiation in β-actin-SRG3 Tg mice during EAE was associated with an increase in the basophil and mast cell populations and in IL4 production. Furthermore, the increased frequency of Treg cells in the spinal cord of β-actin-SRG3 Tg mice might induce the suppression of and accelerate the recovery from EAE symptoms. Taken together, our results provide the first evidence supporting the development of a new therapeutic strategy for EAE involving the modulation of SRG3 expression to induce M2 and Th2 polarization, thereby inhibiting inflammatory immune responses.

No MeSH data available.


Related in: MedlinePlus