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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Clinical Research Institute, Gyeongsang National University Hospital, Jinju, Republic of Korea.
Young-Sool
YS
Hah
Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
Yun-Hong
YH
Cheon
Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
Hye Song
HS
Lim
Clinical Research Institute, Gyeongsang National University Hospital, Jinju, Republic of Korea.
Hee Young
HY
Cho
Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea.
Byung-Hyun
BH
Park
Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea.
Sun-O
SO
Ka
Department of Oral biochmistry, Wonkwang University School of Dentistry, Iksan, Republic of Korea.
Young-Rae
YR
Lee
Clinical Research Institute, Gyeongsang National University Hospital, Jinju, Republic of Korea.
Dong-Won
DW
Jeong
Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
Hyun-Ok
HO
Kim
Department of Microbiology, Chonbuk National University Medical School, Republic of Korea.
Myung-Kwan
MK
Han
Department of Internal Medicine and Institute of Health Science, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
Sang-Il
SI
Lee
D000107:Acetylation; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood* / Q000209:etiology / Q000473:pathology*; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D019426:Integrases / Q000378:metabolism; D007375:Interleukin-1 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D018836:Inflammation Mediators; D007375:Interleukin-1; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C045073:Cre recombinase; D019426:Integrases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1