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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

Infiltration of Treg cells into the spinal cord was dramatically increased in β-actin-SRG3 Tg mice compared to CD2-SRG3 Tg mice during EAE pathogenesis.(A) Splenocytes and (B) MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (upper panel). Alternatively, splenocytes and MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and β-actin-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (lower panel). The mean values ± SD are shown (n = 5; *P<0.05).
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pone.0132329.g007: Infiltration of Treg cells into the spinal cord was dramatically increased in β-actin-SRG3 Tg mice compared to CD2-SRG3 Tg mice during EAE pathogenesis.(A) Splenocytes and (B) MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (upper panel). Alternatively, splenocytes and MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and β-actin-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (lower panel). The mean values ± SD are shown (n = 5; *P<0.05).

Mentions: Recently, it has been reported that Treg cells play a vital role in maintaining the homeostasis of the immune system during EAE development [20, 21]. Thus, we examined whether the discrepant outcome between CD2-SRG3 and β-actin-SRG3 Tg mice is attributable to a difference in the Treg cell frequencies among the CD4+ T cells in the spleen and the spinal cord. We found that no significant difference in the splenic Treg cell populations between the CD2-SRG3 and β-actin-SRG3 Tg mice. However, interestingly, after EAE induction, the frequency of spinal cord-infiltrating Treg cells was significantly increased in the β-actin-SRG3/MBP TCR double Tg mice but was dramatically reduced in the CD2-SRG3/MBP TCR double Tg mice compared to the control mice (Fig 7). Recently it has been reported that the imbalance between Th17 and Treg cells critically contributes to development of autoimmune diseases such as arthritis and EAE [33]. To evaluate if this applies to our findings, we measured the frequency of Th17 cells in the spleen and spinal cord and observed that Th17/Treg ratio among CD4+ T cells from both the spleen and spinal cord was significantly increased in CD2-SRG3/MBP TCR double Tg mice but decreased in β-actin-SRG3/MBP TCR double Tg mice compared to MBP TCR Tg control mice (Fig B in S6 Fig). Thus, the contrasting effect of differential SRG3 over-expression on the Treg cell frequency in the spinal cord shows a strong association between the Treg cell phenotype and the severity of EAE pathogenesis.


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)

Infiltration of Treg cells into the spinal cord was dramatically increased in β-actin-SRG3 Tg mice compared to CD2-SRG3 Tg mice during EAE pathogenesis.(A) Splenocytes and (B) MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (upper panel). Alternatively, splenocytes and MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and β-actin-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (lower panel). The mean values ± SD are shown (n = 5; *P<0.05).
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pone.0132329.g007: Infiltration of Treg cells into the spinal cord was dramatically increased in β-actin-SRG3 Tg mice compared to CD2-SRG3 Tg mice during EAE pathogenesis.(A) Splenocytes and (B) MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and CD2-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (upper panel). Alternatively, splenocytes and MNCs were prepared from the spinal cord of both MBP TCR Tg B10.PL mice and β-actin-SRG3/MBP TCR double Tg B10.PL mice immunized with MBP to induce EAE. The percentages of CD25+FoxP3+ Treg cells among the total CD4+ T cell population in splenocytes and MNCs were evaluated via flow cytometry (lower panel). The mean values ± SD are shown (n = 5; *P<0.05).
Mentions: Recently, it has been reported that Treg cells play a vital role in maintaining the homeostasis of the immune system during EAE development [20, 21]. Thus, we examined whether the discrepant outcome between CD2-SRG3 and β-actin-SRG3 Tg mice is attributable to a difference in the Treg cell frequencies among the CD4+ T cells in the spleen and the spinal cord. We found that no significant difference in the splenic Treg cell populations between the CD2-SRG3 and β-actin-SRG3 Tg mice. However, interestingly, after EAE induction, the frequency of spinal cord-infiltrating Treg cells was significantly increased in the β-actin-SRG3/MBP TCR double Tg mice but was dramatically reduced in the CD2-SRG3/MBP TCR double Tg mice compared to the control mice (Fig 7). Recently it has been reported that the imbalance between Th17 and Treg cells critically contributes to development of autoimmune diseases such as arthritis and EAE [33]. To evaluate if this applies to our findings, we measured the frequency of Th17 cells in the spleen and spinal cord and observed that Th17/Treg ratio among CD4+ T cells from both the spleen and spinal cord was significantly increased in CD2-SRG3/MBP TCR double Tg mice but decreased in β-actin-SRG3/MBP TCR double Tg mice compared to MBP TCR Tg control mice (Fig B in S6 Fig). Thus, the contrasting effect of differential SRG3 over-expression on the Treg cell frequency in the spinal cord shows a strong association between the Treg cell phenotype and the severity of EAE pathogenesis.

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