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SIRT1 deacetylates RORγt and enhances Th17 cell generation.

Lim HW, Kang SG, Ryu JK, Schilling B, Fei M, Lee IS, Kehasse A, Shirakawa K, Yokoyama M, Schnölzer M, Kasler HG, Kwon HS, Gibson BW, Sato H, Akassoglou K, Xiao C, Littman DR, Ott M, Verdin E - J. Exp. Med. (2015)

Bottom Line: Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis.Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis.Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.

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Deletion of SIRT1 in T cells or chemical inhibition of SIRT1 protects mice from EAE. (A) EAE clinical scores of WT and Sirt1−/− mice after MOG35-55 peptide immunization. (B) EAE clinical scores of WT mice immunized with MOG35-55 peptide followed by treatment with DMSO or Ex-527 at 0, 1, and 2 d after immunization. (C) Representative histological sections of spinal cords of DMSO (left) and Ex-527–treated mice (right) from (B). 28 d after immunization, panels were stained for demyelination (LFB/PAS) and lymphocytic infiltration (H&E). Bars, 200 µm. (D) Quantification of demyelination (left) and number of inflammatory foci (right) for DMSO and Ex-527–treated mice. (E) Quantification of spinal cord infiltrated T cell subsets from DMSO and Ex-527 treated mice. (F–H) WT: Sirt1−/− mixed hematopoietic chimeras were immunized with MOG35-55 peptide. Relative CD4 T cell ratio of Sirt1−/− to WT was calculated (F), spinal cords were analyzed for Foxp3+ and IL-17A+ CD4 T cells (G), or Foxp3+ CD4 T cells producing the indicated cytokines (H) were examined, when the mice reached an EAE clinical score of 3. Error bars represent mean ±SEM. Combined data from two (A; 15 mice/each experiment) and three (B; 5–10 mice/each experiment and F, total 10 mice) independent experiments are shown. Representative or combined data from four (C and D), five (E and H), and seven (G, left) mice are shown. *, P < 0.05, **, P < 0.01.
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fig5: Deletion of SIRT1 in T cells or chemical inhibition of SIRT1 protects mice from EAE. (A) EAE clinical scores of WT and Sirt1−/− mice after MOG35-55 peptide immunization. (B) EAE clinical scores of WT mice immunized with MOG35-55 peptide followed by treatment with DMSO or Ex-527 at 0, 1, and 2 d after immunization. (C) Representative histological sections of spinal cords of DMSO (left) and Ex-527–treated mice (right) from (B). 28 d after immunization, panels were stained for demyelination (LFB/PAS) and lymphocytic infiltration (H&E). Bars, 200 µm. (D) Quantification of demyelination (left) and number of inflammatory foci (right) for DMSO and Ex-527–treated mice. (E) Quantification of spinal cord infiltrated T cell subsets from DMSO and Ex-527 treated mice. (F–H) WT: Sirt1−/− mixed hematopoietic chimeras were immunized with MOG35-55 peptide. Relative CD4 T cell ratio of Sirt1−/− to WT was calculated (F), spinal cords were analyzed for Foxp3+ and IL-17A+ CD4 T cells (G), or Foxp3+ CD4 T cells producing the indicated cytokines (H) were examined, when the mice reached an EAE clinical score of 3. Error bars represent mean ±SEM. Combined data from two (A; 15 mice/each experiment) and three (B; 5–10 mice/each experiment and F, total 10 mice) independent experiments are shown. Representative or combined data from four (C and D), five (E and H), and seven (G, left) mice are shown. *, P < 0.05, **, P < 0.01.

Mentions: We next evaluated whether interfering with SIRT1 function in T cells could ameliorate disease progression in a Th17 cell–dependent animal model of autoimmunity. Experimental autoimmune encephalomyelitis (EAE) is a mouse model for human multiple sclerosis (MS), which develops in response to immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide in complete Freund’s adjuvant. Sirt1−/− mice were significantly protected from EAE compared with littermate controls (Fig. 5 A). Treatment with Ex-527 (10 mg/kg, subcutaneous injection) in WT mice was even more effective at ameliorating EAE, not only lessening ultimate disease severity but also significantly delaying its onset (Fig. 5 B). Spinal cords from Ex-527 treated mice exhibited markedly less lymphocytic infiltration and demyelination compared with vehicle-treated controls (Fig. 5, C–E).


SIRT1 deacetylates RORγt and enhances Th17 cell generation.

Lim HW, Kang SG, Ryu JK, Schilling B, Fei M, Lee IS, Kehasse A, Shirakawa K, Yokoyama M, Schnölzer M, Kasler HG, Kwon HS, Gibson BW, Sato H, Akassoglou K, Xiao C, Littman DR, Ott M, Verdin E - J. Exp. Med. (2015)

Deletion of SIRT1 in T cells or chemical inhibition of SIRT1 protects mice from EAE. (A) EAE clinical scores of WT and Sirt1−/− mice after MOG35-55 peptide immunization. (B) EAE clinical scores of WT mice immunized with MOG35-55 peptide followed by treatment with DMSO or Ex-527 at 0, 1, and 2 d after immunization. (C) Representative histological sections of spinal cords of DMSO (left) and Ex-527–treated mice (right) from (B). 28 d after immunization, panels were stained for demyelination (LFB/PAS) and lymphocytic infiltration (H&E). Bars, 200 µm. (D) Quantification of demyelination (left) and number of inflammatory foci (right) for DMSO and Ex-527–treated mice. (E) Quantification of spinal cord infiltrated T cell subsets from DMSO and Ex-527 treated mice. (F–H) WT: Sirt1−/− mixed hematopoietic chimeras were immunized with MOG35-55 peptide. Relative CD4 T cell ratio of Sirt1−/− to WT was calculated (F), spinal cords were analyzed for Foxp3+ and IL-17A+ CD4 T cells (G), or Foxp3+ CD4 T cells producing the indicated cytokines (H) were examined, when the mice reached an EAE clinical score of 3. Error bars represent mean ±SEM. Combined data from two (A; 15 mice/each experiment) and three (B; 5–10 mice/each experiment and F, total 10 mice) independent experiments are shown. Representative or combined data from four (C and D), five (E and H), and seven (G, left) mice are shown. *, P < 0.05, **, P < 0.01.
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fig5: Deletion of SIRT1 in T cells or chemical inhibition of SIRT1 protects mice from EAE. (A) EAE clinical scores of WT and Sirt1−/− mice after MOG35-55 peptide immunization. (B) EAE clinical scores of WT mice immunized with MOG35-55 peptide followed by treatment with DMSO or Ex-527 at 0, 1, and 2 d after immunization. (C) Representative histological sections of spinal cords of DMSO (left) and Ex-527–treated mice (right) from (B). 28 d after immunization, panels were stained for demyelination (LFB/PAS) and lymphocytic infiltration (H&E). Bars, 200 µm. (D) Quantification of demyelination (left) and number of inflammatory foci (right) for DMSO and Ex-527–treated mice. (E) Quantification of spinal cord infiltrated T cell subsets from DMSO and Ex-527 treated mice. (F–H) WT: Sirt1−/− mixed hematopoietic chimeras were immunized with MOG35-55 peptide. Relative CD4 T cell ratio of Sirt1−/− to WT was calculated (F), spinal cords were analyzed for Foxp3+ and IL-17A+ CD4 T cells (G), or Foxp3+ CD4 T cells producing the indicated cytokines (H) were examined, when the mice reached an EAE clinical score of 3. Error bars represent mean ±SEM. Combined data from two (A; 15 mice/each experiment) and three (B; 5–10 mice/each experiment and F, total 10 mice) independent experiments are shown. Representative or combined data from four (C and D), five (E and H), and seven (G, left) mice are shown. *, P < 0.05, **, P < 0.01.
Mentions: We next evaluated whether interfering with SIRT1 function in T cells could ameliorate disease progression in a Th17 cell–dependent animal model of autoimmunity. Experimental autoimmune encephalomyelitis (EAE) is a mouse model for human multiple sclerosis (MS), which develops in response to immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide in complete Freund’s adjuvant. Sirt1−/− mice were significantly protected from EAE compared with littermate controls (Fig. 5 A). Treatment with Ex-527 (10 mg/kg, subcutaneous injection) in WT mice was even more effective at ameliorating EAE, not only lessening ultimate disease severity but also significantly delaying its onset (Fig. 5 B). Spinal cords from Ex-527 treated mice exhibited markedly less lymphocytic infiltration and demyelination compared with vehicle-treated controls (Fig. 5, C–E).

Bottom Line: Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis.Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis.Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158 Gladstone Institute of Virology and Immunology, Gladstone Institute of Neurological Disease, School of Medecine, Department of Neurology, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158.

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Related in: MedlinePlus