Myeloid Deletion Of SIRT1 Aggravates Serum Transfer Arthritis But Ameliorate Collagen-Induced Arthritis

Sang-Il Lee¹, Yun-Hong Cheon², Won Seok Lee² and Ji-Min Kim³, ¹Division of Rheumatology, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, South Korea, ²Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Jeonju, South Korea, ³Division of Rheumatology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Animal models, Collagen, osteoclasts, rheumatoid arthritis (RA) and rheumatoid arthritis

Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis I

Session Type: Abstract Submissions (ACR)

Background/Purpose: SIRT1 plays a pivotal role in regulating the inflammatory response. Thus, we assessed the role of SIRT1 in K/BxN serum transfer arthritis as a model of inflammatory arthritis using a myeloid cell-specific SIRT1 knockout (mSIRT1 KO) mouse. To further understand how SIRT1 regulates autoimmunity, we also evaluated collagen-induced arthritis (CIA) using mSIRT1 KO mice.

Methods: mSIRT1 KO mice were generated by using the loxP/Cre recombinase system. K/BxN serum transfer arthritis and CIA were induced in mSIRT1 KO (SIRT1^loxP/loxPLysM-Cre^+/+) and their age-matched littermate loxP control (SIRT1^loxP/loxPLysM-Cre^-/-) mice. Arthritis severity was assessed by clinical and pathological scoring. The levels of inflammatory cytokines in the serum and joints were measured by ELISA and quantitative polymerase chain reaction. The migration, M1 polarization, cytokine production, osteoclastogenesis, and p65 acetylation were assessed in bone marrow-derived monocytes/macrophages (BMMs). The each subset of T cells and dendritic cells was analyzed by flow cytofluorometry in lymph node and spleen.

Results: The mSIRT1 KO mice showed more severe inflammatory arthritis accompanied by aggravated pathological findings than control in K/BxN serum transfer model. These effects were paralleled by higher levels of IL-1 and TNF-α and increased TRAP-positive osteoclasts and F4/80⁺ macrophages in the synovium of mSIRT1 KO mice. BMMs from the mSIRT1 mice displayed hyperacetylated p65 and increased NF-κB binding activity than control. However, unlike passive K/BxN arthritis, SIRT1 deficiency in CIA was associated with lower arthritic, radiographic, and pathologic severity. These effects were paralleled by lower levels of numerous inflammatory cytokines in the ankles and lymph nodes of mSIRT1 KO mice. In CIA, the proportion of Th1 and Th17 cells and CD80/86-positive dendritic cells was significantly decreased in mSIRT1 KO mice than controls.

Conclusion: Our study suggests that SIRT1 plays a complex role in regulating inflammation and adaptive immunity and, depending on the model, either enhances or suppresses rheumatoid arthritis.

Disclosure:

S. I. Lee,
None;

Y. H. Cheon,
None;

W. S. Lee,
None;

J. M. Kim,
None.

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