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SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis.

Lo Sasso G, Menzies KJ, Mottis A, Piersigilli A, Perino A, Yamamoto H, Schoonjans K, Auwerx J - PLoS ONE (2014)

Bottom Line: Notably, under basal condition, Sirt2 deficiency does not affect the basal phenotype and intestinal morphology Sirt2 deficiency, however, affects macrophage polarization, creating a pro-inflammatory milieu in the immune cells compartment.In fact, SIRT2 deletion promotes inflammatory responses by increasing NF-κB acetylation and by reducing the M2-associated anti-inflammatory pathway.Finally, we speculate that the activation of SIRT2 may be a potential approach for the treatment of inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

ABSTRACT

Background: SIRT2 belongs to a highly conserved family of NAD+-dependent deacylases, consisting of seven members (SIRT1-SIRT7), which vary in subcellular localizations and have substrates ranging from histones to transcription factors and enzymes. Recently SIRT2 was revealed to play an important role in inflammation, directly binding, deacetylating, and inhibiting the p65 subunit of NF-κB.

Methods: A Sirt2 deficient mouse line (Sirt2-/-) was generated by deleting exons 5-7, encoding part of the SIRT2 deacetylase domain, by homologous recombination. Age- and sex-matched Sirt2-/- and Sirt2+/+ littermate mice were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility.

Results: Sirt2-/- mice displayed more severe clinical and histological manifestations after DSS colitis compared to wild type littermates. Notably, under basal condition, Sirt2 deficiency does not affect the basal phenotype and intestinal morphology Sirt2 deficiency, however, affects macrophage polarization, creating a pro-inflammatory milieu in the immune cells compartment.

Conclusion: These data confirm a protective role for SIRT2 against the development of inflammatory processes, pointing out a potential role for this sirtuin as a suppressor of colitis. In fact, SIRT2 deletion promotes inflammatory responses by increasing NF-κB acetylation and by reducing the M2-associated anti-inflammatory pathway. Finally, we speculate that the activation of SIRT2 may be a potential approach for the treatment of inflammatory bowel disease.

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Plasma cytokine levels and cytokine mRNA levels in the colon of Sirt2−/− mice with DSS-induced colitis.(A–C) Measurements of serum cytokine levels in Sirt2+/+ (+/+) and Sirt2−/− (−/−) mice after DSS-induced colitis; TNFα (A), IL1β (B), and IL6 (C). (D–E) Cytokine mRNA levels in the colon of Sirt2+/+ and Sirt2−/− mice before and after DSS-induced colitis. Tnfα (D), Il1β (E), and Il6 (F). (G–H) mRNA levels of the genes related to maintenance of intestinal permeability, Ocln (G), Cldn1 (H), Zo1(I) in Sirt2+/+ and Sirt2−/− mice with or without DSS treatment. n = 10/group (with DSS treatment); n = 5/group (without DSS treatment). Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.
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pone-0103573-g005: Plasma cytokine levels and cytokine mRNA levels in the colon of Sirt2−/− mice with DSS-induced colitis.(A–C) Measurements of serum cytokine levels in Sirt2+/+ (+/+) and Sirt2−/− (−/−) mice after DSS-induced colitis; TNFα (A), IL1β (B), and IL6 (C). (D–E) Cytokine mRNA levels in the colon of Sirt2+/+ and Sirt2−/− mice before and after DSS-induced colitis. Tnfα (D), Il1β (E), and Il6 (F). (G–H) mRNA levels of the genes related to maintenance of intestinal permeability, Ocln (G), Cldn1 (H), Zo1(I) in Sirt2+/+ and Sirt2−/− mice with or without DSS treatment. n = 10/group (with DSS treatment); n = 5/group (without DSS treatment). Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.

Mentions: Pro-inflammatory cytokines such as TNFα, IL1β, and IL6 play pivotal roles in the pathogenesis of colitis [18]. Since colitis is a systemic inflammatory disease, we measured cytokine levels in the plasma of Sirt2+/+ and Sirt2−/− mice, during basal conditions and after DSS treatment. Under normal conditions both genotypes of mice showed similar levels of plasma cytokines (Figure 5A–C). However, after DSS treatment, plasma levels of TNFα and IL1β were more elevated in Sirt2−/− mice, compared to the Sirt2+/+ animals (Figure 5A–B), whereas IL6 levels, although increased by DSS treatment, remained indistinguishable between the two genotypes (Figure 5C). Unlike the plasma cytokine levels, the colon mRNA levels of Tnfα and Il1β were already modestly higher in Sirt2−/− mice in basal conditions (Figure 5D–E). Following DSS, an induction in the expression of the mRNAs coding for these cytokines occurred in both genotypes; however, only the induction of Tnfα transcript was significantly different in Sirt2−/− from Sirt2+/+ mice (Figure 5D). Notably, Il6 mRNA levels were again indistinguishable between both genotypes, both before and after DSS (Figure 5F).


SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis.

Lo Sasso G, Menzies KJ, Mottis A, Piersigilli A, Perino A, Yamamoto H, Schoonjans K, Auwerx J - PLoS ONE (2014)

Plasma cytokine levels and cytokine mRNA levels in the colon of Sirt2−/− mice with DSS-induced colitis.(A–C) Measurements of serum cytokine levels in Sirt2+/+ (+/+) and Sirt2−/− (−/−) mice after DSS-induced colitis; TNFα (A), IL1β (B), and IL6 (C). (D–E) Cytokine mRNA levels in the colon of Sirt2+/+ and Sirt2−/− mice before and after DSS-induced colitis. Tnfα (D), Il1β (E), and Il6 (F). (G–H) mRNA levels of the genes related to maintenance of intestinal permeability, Ocln (G), Cldn1 (H), Zo1(I) in Sirt2+/+ and Sirt2−/− mice with or without DSS treatment. n = 10/group (with DSS treatment); n = 5/group (without DSS treatment). Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4114785&req=5

pone-0103573-g005: Plasma cytokine levels and cytokine mRNA levels in the colon of Sirt2−/− mice with DSS-induced colitis.(A–C) Measurements of serum cytokine levels in Sirt2+/+ (+/+) and Sirt2−/− (−/−) mice after DSS-induced colitis; TNFα (A), IL1β (B), and IL6 (C). (D–E) Cytokine mRNA levels in the colon of Sirt2+/+ and Sirt2−/− mice before and after DSS-induced colitis. Tnfα (D), Il1β (E), and Il6 (F). (G–H) mRNA levels of the genes related to maintenance of intestinal permeability, Ocln (G), Cldn1 (H), Zo1(I) in Sirt2+/+ and Sirt2−/− mice with or without DSS treatment. n = 10/group (with DSS treatment); n = 5/group (without DSS treatment). Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.
Mentions: Pro-inflammatory cytokines such as TNFα, IL1β, and IL6 play pivotal roles in the pathogenesis of colitis [18]. Since colitis is a systemic inflammatory disease, we measured cytokine levels in the plasma of Sirt2+/+ and Sirt2−/− mice, during basal conditions and after DSS treatment. Under normal conditions both genotypes of mice showed similar levels of plasma cytokines (Figure 5A–C). However, after DSS treatment, plasma levels of TNFα and IL1β were more elevated in Sirt2−/− mice, compared to the Sirt2+/+ animals (Figure 5A–B), whereas IL6 levels, although increased by DSS treatment, remained indistinguishable between the two genotypes (Figure 5C). Unlike the plasma cytokine levels, the colon mRNA levels of Tnfα and Il1β were already modestly higher in Sirt2−/− mice in basal conditions (Figure 5D–E). Following DSS, an induction in the expression of the mRNAs coding for these cytokines occurred in both genotypes; however, only the induction of Tnfα transcript was significantly different in Sirt2−/− from Sirt2+/+ mice (Figure 5D). Notably, Il6 mRNA levels were again indistinguishable between both genotypes, both before and after DSS (Figure 5F).

Bottom Line: Notably, under basal condition, Sirt2 deficiency does not affect the basal phenotype and intestinal morphology Sirt2 deficiency, however, affects macrophage polarization, creating a pro-inflammatory milieu in the immune cells compartment.In fact, SIRT2 deletion promotes inflammatory responses by increasing NF-κB acetylation and by reducing the M2-associated anti-inflammatory pathway.Finally, we speculate that the activation of SIRT2 may be a potential approach for the treatment of inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

ABSTRACT

Background: SIRT2 belongs to a highly conserved family of NAD+-dependent deacylases, consisting of seven members (SIRT1-SIRT7), which vary in subcellular localizations and have substrates ranging from histones to transcription factors and enzymes. Recently SIRT2 was revealed to play an important role in inflammation, directly binding, deacetylating, and inhibiting the p65 subunit of NF-κB.

Methods: A Sirt2 deficient mouse line (Sirt2-/-) was generated by deleting exons 5-7, encoding part of the SIRT2 deacetylase domain, by homologous recombination. Age- and sex-matched Sirt2-/- and Sirt2+/+ littermate mice were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility.

Results: Sirt2-/- mice displayed more severe clinical and histological manifestations after DSS colitis compared to wild type littermates. Notably, under basal condition, Sirt2 deficiency does not affect the basal phenotype and intestinal morphology Sirt2 deficiency, however, affects macrophage polarization, creating a pro-inflammatory milieu in the immune cells compartment.

Conclusion: These data confirm a protective role for SIRT2 against the development of inflammatory processes, pointing out a potential role for this sirtuin as a suppressor of colitis. In fact, SIRT2 deletion promotes inflammatory responses by increasing NF-κB acetylation and by reducing the M2-associated anti-inflammatory pathway. Finally, we speculate that the activation of SIRT2 may be a potential approach for the treatment of inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus