SIRT6 stabilization and cytoplasmic localization in macrophages regulates acute and chronic inflammation in mice
Posted by Ernesto on Wednesday, 4 June 2025
Autores:
Mariana Bresque 1 , Karina Cal 2 , Valentina Pérez-Torrado 3 , Laura Colman 4 , Jorge Rodríguez-Duarte 5 , Cecilia Vilaseca 6 , Leonardo Santos 7 , María Pía Garat 7 , Santiago Ruiz 7 , Frances Evans 8 , Rosina Dapueto 1 , Paola Contreras 9 , Aldo Calliari 2 , Carlos Escande 10
Revista (o libro):
J Biol Chem
Año:
2022
Mes-dia:
0300
issue, vol, paginas, etc:
298(3):101711
doi:
10.1016/j.jbc.2022.101711
PMID:
35150745
Abstract:
Acute and chronic inflammations are key homeostatic events in health and disease. Sirtuins (SIRTs), a family of NAD-dependent protein deacylases, play a pivotal role in the regulation of these inflammatory responses. Indeed, SIRTs have anti-inflammatory effects through a myriad of signaling cascades, including histone deacetylation and gene silencing, p65/RelA deacetylation and inactivation, and nucleotide‑binding oligomerization domain, leucine rich repeat, and pyrin domain‑containing protein 3 inflammasome inhibition. Nevertheless, recent findings show that SIRTs, specifically SIRT6, are also necessary for mounting an active inflammatory response in macrophages. SIRT6 has been shown to positively regulate tumor necrosis factor alpha (TNFα) secretion by demyristoylating pro-TNFα in the cytoplasm. However, how SIRT6, a nuclear chromatin-binding protein, fulfills this function in the cytoplasm is currently unknown. Herein, we show by Western blot and immunofluorescence that in macrophages and fibroblasts there is a subpopulation of SIRT6 that is highly unstable and quickly degraded via the proteasome. Upon lipopolysaccharide stimulation in Raw 264.7, bone marrow, and peritoneal macrophages, this population of SIRT6 is rapidly stabilized and localizes in the cytoplasm, specifically in the vicinity of the endoplasmic reticulum, promoting TNFα secretion. Furthermore, we also found that acute SIRT6 inhibition dampens TNFα secretion both in vitro and in vivo, decreasing lipopolysaccharide-induced septic shock. Finally, we tested SIRT6 relevance in systemic inflammation using an obesity-induced chronic inflammatory in vivo model, where TNFα plays a key role, and we show that short-term genetic deletion of SIRT6 in macrophages of obese mice ameliorated systemic inflammation and hyperglycemia, suggesting that SIRT6 plays an active role in inflammation-mediated glucose intolerance during obesity.
Afiliaciones:
1 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay; Laboratory of Vascular Biology and Drug Development, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay.
2 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay; Departamento de Biociencias, Facultad de Veterinaria, Universidad de la República (UdelaR), Montevideo, Uruguay.
3 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay; Departamento de Inmunobiología, Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay; Área Inmunología, Departamento de Biociencias, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay.
4 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay; Departamento de Química Orgánica, Facultad de Química, Universidad de la República (UdelaR), Montevideo, Uruguay.
5 Laboratory of Vascular Biology and Drug Development, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay.
6 Departamento de Fisiología, Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay.
7 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay.
8 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay; Laboratory of Neuroinflammation and Gene Therapy, Institut Pasteur Montevideo, Montevideo, Uruguay.
9 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay; Departamento de Fisiología, Facultad de Medicina, Universidad de la República (UdelaR), Montevideo, Uruguay.
10 Laboratory of Metabolic Diseases and Aging, INDICYO Program, Institut Pasteur Montevideo, Montevideo, Uruguay. Electronic address: escande@pasteur.edu.uy.
Enlace pubmed:
https://pubmed.ncbi.nlm.nih.gov/35150745/
Enlace full text:
https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(22)00151-X
Cita:
Bresque M, Cal K, Pérez-Torrado V, Colman L, Rodríguez-Duarte J, Vilaseca C, Santos L, Garat MP, Ruiz S, Evans F, Dapueto R, Contreras P, Calliari A, Escande C. SIRT6 stabilization and cytoplasmic localization in macrophages regulates acute and chronic inflammation in mice. J Biol Chem. 2022 Mar;298(3):101711. doi: 10.1016/j.jbc.2022.101711. Epub 2022 Feb 9. PMID: 35150745; PMCID: PMC8913316.