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Blockage of indoleamine 2,3-dioxygenase regulates Japanese encephalitis via enhancement of type I/II IFN innate and adaptive T-cell responses.

Kim SB, Choi JY, Uyangaa E, Patil AM, Hossain FM, Hur J, Park SY, Lee JH, Kim K, Eo SK - J Neuroinflammation (2016)

Bottom Line: Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function.Furthermore, inhibition of IDO activity enhanced resistance to JE, reduced the viral burden in lymphoid and CNS tissues, and resulted in early and increased CNS infiltration by Ly-6C(hi) monocytes, NK, CD4(+), and CD8(+) T-cells.Therefore, our data provide valuable insight into the use of IDO inhibition by specific inhibitors as a promising tool for therapeutic and prophylactic strategies against viral encephalitis caused by neurotropic viruses.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, 54596, Republic of Korea.

ABSTRACT

Background: Japanese encephalitis (JE), a leading cause of viral encephalitis, is characterized by extensive neuroinflammation following infection with neurotropic JE virus (JEV). Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function. Although the regulatory role of IDO in viral replication has been postulated, the in vivo role of IDO activity has not been fully addressed in neurotropic virus-caused encephalitis.

Methods: Mice in which IDO activity was inhibited by genetic ablation or using a specific inhibitor were examined for mortality and clinical signs after infection. Neuroinflammation was evaluated by central nervous system (CNS) infiltration of leukocytes and cytokine expression. IDO expression, viral burden, JEV-specific T-cell, and type I/II interferon (IFN-I/II) innate responses were also analyzed.

Results: Elevated expression of IDO activity in myeloid and neuron cells of the lymphoid and CNS tissues was closely associated with clinical signs of JE. Furthermore, inhibition of IDO activity enhanced resistance to JE, reduced the viral burden in lymphoid and CNS tissues, and resulted in early and increased CNS infiltration by Ly-6C(hi) monocytes, NK, CD4(+), and CD8(+) T-cells. JE amelioration in IDO-ablated mice was also associated with enhanced NK and JEV-specific T-cell responses. More interestingly, IDO ablation induced rapid enhancement of type I IFN (IFN-I) innate responses in CD11c(+) dendritic cells (DCs), including conventional and plasmacytoid DCs, following JEV infection. This enhanced IFN-I innate response in IDO-ablated CD11c(+) DCs was coupled with strong induction of PRRs (RIG-I, MDA5), transcription factors (IRF7, STAT1), and antiviral ISG genes (Mx1, Mx2, ISG49, ISG54, ISG56). IDO ablation also enhanced the IFN-I innate response in neuron cells, which may delay the spread of virus in the CNS. Finally, we identified that IDO ablation in myeloid cells derived from hematopoietic stem cells (HSCs) dominantly contributed to JE amelioration and that HSC-derived leukocytes played a key role in the enhanced IFN-I innate responses in the IDO-ablated environment.

Conclusions: Inhibition of IDO activity ameliorated JE via enhancement of antiviral IFN-I/II innate and adaptive T-cell responses and increased CNS infiltration of peripheral leukocytes. Therefore, our data provide valuable insight into the use of IDO inhibition by specific inhibitors as a promising tool for therapeutic and prophylactic strategies against viral encephalitis caused by neurotropic viruses.

No MeSH data available.


Related in: MedlinePlus

IDO induces a skewed IFN-γ+CD4+ T-cell response during JE. a, b The frequency and number of CD4+Foxp3+ Tregs in the spleen of IDO-ablated mice. The frequency (a) and absolute number (b) of CD4+Foxp3+ Treg cells in the spleen of wild-type and IDO KO mice were determined by flow cytometric analysis 5 dpi. The values in the representative dot plots show the average percentage of CD25+Foxp3+ cells in CD4+ T-cells; the bar charts denote the average number ± SD of CD4+Foxp3+ Tregs in the spleen derived from at least four mice per group. c, d The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen of IDO-ablated mice. The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells were determined by intracellular cytokine staining of the splenocytes prepared from wild-type and IDO KO mice 5 dpi in response to PMA + ionomycin stimulation. The values in the representative dot plots show the average percentage of the indicated cell populations after gating on CD4+ T-cells; the bar charts denote the average number ± SD of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen derived from at least four mice per group. **p < 0.01 compared with levels in the indicated groups
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Fig6: IDO induces a skewed IFN-γ+CD4+ T-cell response during JE. a, b The frequency and number of CD4+Foxp3+ Tregs in the spleen of IDO-ablated mice. The frequency (a) and absolute number (b) of CD4+Foxp3+ Treg cells in the spleen of wild-type and IDO KO mice were determined by flow cytometric analysis 5 dpi. The values in the representative dot plots show the average percentage of CD25+Foxp3+ cells in CD4+ T-cells; the bar charts denote the average number ± SD of CD4+Foxp3+ Tregs in the spleen derived from at least four mice per group. c, d The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen of IDO-ablated mice. The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells were determined by intracellular cytokine staining of the splenocytes prepared from wild-type and IDO KO mice 5 dpi in response to PMA + ionomycin stimulation. The values in the representative dot plots show the average percentage of the indicated cell populations after gating on CD4+ T-cells; the bar charts denote the average number ± SD of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen derived from at least four mice per group. **p < 0.01 compared with levels in the indicated groups

Mentions: CD4+CD25+Foxp3+ Treg cells may contribute to controlling lethal neuroinflammation caused by neurotropic viruses [44]. In contrast, IL-17+CD4+ Th17 cells play a critical role in autoimmune and virus-caused immunopathologic diseases by facilitating pathologic consequences through neutrophil recruitment [45, 46]. The generation of CD4+CD25+Foxp3+ Tregs is reciprocally linked with IL-17+CD4+ Th17 and IFN-γ+CD4+ Th1 cells [47, 48]. Because IDO may regulate the equilibrium of CD4+Foxp3+ Tregs and IL-17+CD4+ Th17 cells in inflammatory diseases [49, 50], we examined the generation of each CD4+ Th subset, including CD4+Foxp3+ Tregs, IL-17+CD4+ Th17, and IFN-γ+CD4+ Th1 cells, early during JE progression. Our results revealed that IDO-ablated mice showed no significant alterations in the frequency or number of CD4+CD25+Foxp3+ Tregs, compared to wild-type BL/6 mice (Fig. 6a, b). In contrast, IFN-γ+CD4+ Th1 cells were detected at higher levels in IDO-ablated mice, and the frequency and number of IL-17+CD4+ Th17 cells were not changed by IDO ablation (Fig. 6c, d). Therefore, this result suggests that the increase in IFN-γ+CD4+ Th1 cells in IDO-ablated mice contributes in part to the control of JE progression during the early stage of infection.Fig. 6


Blockage of indoleamine 2,3-dioxygenase regulates Japanese encephalitis via enhancement of type I/II IFN innate and adaptive T-cell responses.

Kim SB, Choi JY, Uyangaa E, Patil AM, Hossain FM, Hur J, Park SY, Lee JH, Kim K, Eo SK - J Neuroinflammation (2016)

IDO induces a skewed IFN-γ+CD4+ T-cell response during JE. a, b The frequency and number of CD4+Foxp3+ Tregs in the spleen of IDO-ablated mice. The frequency (a) and absolute number (b) of CD4+Foxp3+ Treg cells in the spleen of wild-type and IDO KO mice were determined by flow cytometric analysis 5 dpi. The values in the representative dot plots show the average percentage of CD25+Foxp3+ cells in CD4+ T-cells; the bar charts denote the average number ± SD of CD4+Foxp3+ Tregs in the spleen derived from at least four mice per group. c, d The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen of IDO-ablated mice. The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells were determined by intracellular cytokine staining of the splenocytes prepared from wild-type and IDO KO mice 5 dpi in response to PMA + ionomycin stimulation. The values in the representative dot plots show the average percentage of the indicated cell populations after gating on CD4+ T-cells; the bar charts denote the average number ± SD of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen derived from at least four mice per group. **p < 0.01 compared with levels in the indicated groups
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4835894&req=5

Fig6: IDO induces a skewed IFN-γ+CD4+ T-cell response during JE. a, b The frequency and number of CD4+Foxp3+ Tregs in the spleen of IDO-ablated mice. The frequency (a) and absolute number (b) of CD4+Foxp3+ Treg cells in the spleen of wild-type and IDO KO mice were determined by flow cytometric analysis 5 dpi. The values in the representative dot plots show the average percentage of CD25+Foxp3+ cells in CD4+ T-cells; the bar charts denote the average number ± SD of CD4+Foxp3+ Tregs in the spleen derived from at least four mice per group. c, d The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen of IDO-ablated mice. The frequency and number of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells were determined by intracellular cytokine staining of the splenocytes prepared from wild-type and IDO KO mice 5 dpi in response to PMA + ionomycin stimulation. The values in the representative dot plots show the average percentage of the indicated cell populations after gating on CD4+ T-cells; the bar charts denote the average number ± SD of IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells in the spleen derived from at least four mice per group. **p < 0.01 compared with levels in the indicated groups
Mentions: CD4+CD25+Foxp3+ Treg cells may contribute to controlling lethal neuroinflammation caused by neurotropic viruses [44]. In contrast, IL-17+CD4+ Th17 cells play a critical role in autoimmune and virus-caused immunopathologic diseases by facilitating pathologic consequences through neutrophil recruitment [45, 46]. The generation of CD4+CD25+Foxp3+ Tregs is reciprocally linked with IL-17+CD4+ Th17 and IFN-γ+CD4+ Th1 cells [47, 48]. Because IDO may regulate the equilibrium of CD4+Foxp3+ Tregs and IL-17+CD4+ Th17 cells in inflammatory diseases [49, 50], we examined the generation of each CD4+ Th subset, including CD4+Foxp3+ Tregs, IL-17+CD4+ Th17, and IFN-γ+CD4+ Th1 cells, early during JE progression. Our results revealed that IDO-ablated mice showed no significant alterations in the frequency or number of CD4+CD25+Foxp3+ Tregs, compared to wild-type BL/6 mice (Fig. 6a, b). In contrast, IFN-γ+CD4+ Th1 cells were detected at higher levels in IDO-ablated mice, and the frequency and number of IL-17+CD4+ Th17 cells were not changed by IDO ablation (Fig. 6c, d). Therefore, this result suggests that the increase in IFN-γ+CD4+ Th1 cells in IDO-ablated mice contributes in part to the control of JE progression during the early stage of infection.Fig. 6

Bottom Line: Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function.Furthermore, inhibition of IDO activity enhanced resistance to JE, reduced the viral burden in lymphoid and CNS tissues, and resulted in early and increased CNS infiltration by Ly-6C(hi) monocytes, NK, CD4(+), and CD8(+) T-cells.Therefore, our data provide valuable insight into the use of IDO inhibition by specific inhibitors as a promising tool for therapeutic and prophylactic strategies against viral encephalitis caused by neurotropic viruses.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, 54596, Republic of Korea.

ABSTRACT

Background: Japanese encephalitis (JE), a leading cause of viral encephalitis, is characterized by extensive neuroinflammation following infection with neurotropic JE virus (JEV). Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function. Although the regulatory role of IDO in viral replication has been postulated, the in vivo role of IDO activity has not been fully addressed in neurotropic virus-caused encephalitis.

Methods: Mice in which IDO activity was inhibited by genetic ablation or using a specific inhibitor were examined for mortality and clinical signs after infection. Neuroinflammation was evaluated by central nervous system (CNS) infiltration of leukocytes and cytokine expression. IDO expression, viral burden, JEV-specific T-cell, and type I/II interferon (IFN-I/II) innate responses were also analyzed.

Results: Elevated expression of IDO activity in myeloid and neuron cells of the lymphoid and CNS tissues was closely associated with clinical signs of JE. Furthermore, inhibition of IDO activity enhanced resistance to JE, reduced the viral burden in lymphoid and CNS tissues, and resulted in early and increased CNS infiltration by Ly-6C(hi) monocytes, NK, CD4(+), and CD8(+) T-cells. JE amelioration in IDO-ablated mice was also associated with enhanced NK and JEV-specific T-cell responses. More interestingly, IDO ablation induced rapid enhancement of type I IFN (IFN-I) innate responses in CD11c(+) dendritic cells (DCs), including conventional and plasmacytoid DCs, following JEV infection. This enhanced IFN-I innate response in IDO-ablated CD11c(+) DCs was coupled with strong induction of PRRs (RIG-I, MDA5), transcription factors (IRF7, STAT1), and antiviral ISG genes (Mx1, Mx2, ISG49, ISG54, ISG56). IDO ablation also enhanced the IFN-I innate response in neuron cells, which may delay the spread of virus in the CNS. Finally, we identified that IDO ablation in myeloid cells derived from hematopoietic stem cells (HSCs) dominantly contributed to JE amelioration and that HSC-derived leukocytes played a key role in the enhanced IFN-I innate responses in the IDO-ablated environment.

Conclusions: Inhibition of IDO activity ameliorated JE via enhancement of antiviral IFN-I/II innate and adaptive T-cell responses and increased CNS infiltration of peripheral leukocytes. Therefore, our data provide valuable insight into the use of IDO inhibition by specific inhibitors as a promising tool for therapeutic and prophylactic strategies against viral encephalitis caused by neurotropic viruses.

No MeSH data available.


Related in: MedlinePlus