Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-κB activation

• Published in: PloS one Vol. 9; no. 2; p. e87733
• Main Authors: Hah, Young-Sool, Cheon, Yun-Hong, Lim, Hye Song, Cho, Hee Young, Park, Byung-Hyun, Ka, Sun-O, Lee, Young-Rae, Jeong, Dong-Won, Kim, Hyun-Ok, Han, Myung-Kwan, Lee, Sang-Il
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.02.2014; Public Library of Science (PLoS)
• Subjects: Acetylation; Acid phosphatase (tartrate-resistant); Activation; Animals; Ankle; Apoptosis; Arthritis; Arthritis, Experimental - blood; Arthritis, Experimental - etiology; Arthritis, Experimental - pathology; Biochemistry; Biocompatibility; Biology; Biomedical materials; Blotting, Western; Bone marrow; Cell Movement; Cells, Cultured; Clonal deletion; Collagen; Cre recombinase; Cytokines; Dendritic cells; Diabetes; Electrophoretic Mobility Shift Assay; Enzyme-linked immunosorbent assay; Fibroblasts; Fluorescent Antibody Technique; Hospitals; Humans; In vivo methods and tests; Inflammation; Inflammation Mediators - blood; Inflammatory response; Integrases - metabolism; Interleukin 1; Interleukin-1 - blood; Internal medicine; Joint diseases; Kinases; Macrophages; Medical schools; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Migration; Monocytes; Monocytes - metabolism; Monocytes - pathology; Myeloid Cells - metabolism; Myeloid Cells - pathology; NF-κB protein; Osteoclastogenesis; Osteoclasts; Polarization; Recombinase; Rheumatoid arthritis; Rodents; Signal Transduction; Signaling; SIRT1 protein; Sirtuin 1 - physiology; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - blood; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0087733

SIRT1 modulates the acetylation of the p65 subunit of nuclear factor-κB (NF-κB) and plays a pivotal role in the inflammatory response. This study sought to assess the role of SIRT1 in rheumatoid arthritis (RA) using a myeloid cell-specific SIRT1 knockout (mSIRT1 KO) mouse. mSIRT1 KO mice were generated using the loxP/Cre recombinase system. K/BxN serum transfer arthritis was induced in mSIRT1 KO mice and age-matched littermate loxP control mice. Arthritis severity was assessed by clinical and pathological scoring. The levels of inflammatory cytokines in the serum and joints were measured by ELISA. Migration, M1 polarization, cytokine production, osteoclastogenesis, and p65 acetylation were assessed in bone marrow-derived monocytes/macrophages (BMMs). mSIRT1 KO mice showed more severe inflammatory arthritis and aggravated pathological findings than control mice. These effects were paralleled by increases in IL-1, TNF-α, TRAP-positive osteoclasts, and F4/80⁺ macrophages in the ankles of mSIRT1 KO mice. In addition, BMMs from mSIRT1 KO mice displayed hyperacetylated p65 and increased NF-κB binding activity when compared to control mice, which resulted in increased M1 polarization, migration, pro-inflammatory cytokine production, and osteoclastogenesis. Our study provides in vivo evidence that myeloid cell-specific deletion of SIRT1 exacerbates inflammatory arthritis via the hyperactivation of NF-κB signaling, which suggests that SIRT1 activation may be beneficial in the treatment of inflammatory arthritis.