Limits...
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.

Show MeSH

Related in: MedlinePlus

CD4+CD69+ T cells are increased in mesenteric lymph nodes from Sirt2−/− mice with DSS-induced colitis.(A) Representative images of FACS analysis demonstrating TCRb+ cells (left), and their composition sorted by CD4 and CD69 staining (right). (B) The composition of MLNs is compared between Sirt2+/+ and Sirt2−/− mice; TCRb+, CD4+, CD4+CD69−, and CD4+CD69+ cells. n = 10/group. Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4114785&req=5

pone-0103573-g004: CD4+CD69+ T cells are increased in mesenteric lymph nodes from Sirt2−/− mice with DSS-induced colitis.(A) Representative images of FACS analysis demonstrating TCRb+ cells (left), and their composition sorted by CD4 and CD69 staining (right). (B) The composition of MLNs is compared between Sirt2+/+ and Sirt2−/− mice; TCRb+, CD4+, CD4+CD69−, and CD4+CD69+ cells. n = 10/group. Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.

Mentions: Furthermore, the cell composition of mesenteric lymph nodes, as determined by FACS analysis, was distinct between the two genotypes. Although no difference was observed in the total amount of CD4+ T lymphocytes, Sirt2−/− mice had an increased proportion of activated lymphocytes (CD4+/CD69+) compared to the control mice (Figure 4A–B), consistent with an enhanced inflammatory response.


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)

CD4+CD69+ T cells are increased in mesenteric lymph nodes from Sirt2−/− mice with DSS-induced colitis.(A) Representative images of FACS analysis demonstrating TCRb+ cells (left), and their composition sorted by CD4 and CD69 staining (right). (B) The composition of MLNs is compared between Sirt2+/+ and Sirt2−/− mice; TCRb+, CD4+, CD4+CD69−, and CD4+CD69+ cells. n = 10/group. 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-g004: CD4+CD69+ T cells are increased in mesenteric lymph nodes from Sirt2−/− mice with DSS-induced colitis.(A) Representative images of FACS analysis demonstrating TCRb+ cells (left), and their composition sorted by CD4 and CD69 staining (right). (B) The composition of MLNs is compared between Sirt2+/+ and Sirt2−/− mice; TCRb+, CD4+, CD4+CD69−, and CD4+CD69+ cells. n = 10/group. Results are expressed as the mean ± SEM. *P<0.05; **P<0.01; ***P<0.001.
Mentions: Furthermore, the cell composition of mesenteric lymph nodes, as determined by FACS analysis, was distinct between the two genotypes. Although no difference was observed in the total amount of CD4+ T lymphocytes, Sirt2−/− mice had an increased proportion of activated lymphocytes (CD4+/CD69+) compared to the control mice (Figure 4A–B), consistent with an enhanced inflammatory response.

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