Matsumoto Takuya, Takahashi Nobunori, Kojima Toshihisa, Yoshioka Yutaka, Ishikawa Jun, Furukawa Koichi, Ono Kenji, Sawada Makoto, Ishiguro Naoki, Yamamoto Akihito
Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
Department of Oral and Maxillofacial Surgery/Protective Care for Masticatory Disorders, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
Arthritis Res Ther. 2016 Jun 7;18(1):133. doi: 10.1186/s13075-016-1035-9.
The aim of this study was to assess the effects of soluble sialic acid-binding immunoglobulin-type lectin (sSiglec)-9 on joint inflammation and destruction in a murine collagen-induced arthritis (CIA) model and in monolayer cultures of murine macrophages (RAW264.7 cells and peritoneal macrophages) and fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis.
DBA/1J mice were immunized with type II collagen. Effects of sSiglec-9 were evaluated using a physiologic arthritis score, histological analysis, serum tumor necrosis factor (TNF)-α concentration, and the proportion of forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. In vivo biofluorescence imaging was used to assess the distribution of sSiglec-9. Levels of M1 (TNF-α, interleukin [IL]-6, and inducible nitric oxide synthase) and M2 (CD206, Arginase-1, and IL-10) macrophage markers and phosphorylation of intracellular signaling molecules were examined in macrophages, and levels of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 were examined in FLS.
sSiglec-9 significantly suppressed the clinical and histological incidence and severity of arthritis. The proportion of Foxp3-positive Treg cells significantly improved and serum TNF-α concentration decreased in vivo. Although sSiglec-9 reduced the expression of M1 markers in macrophages, it did not affect the expression of M2 markers and MMPs in FLS. Nuclear factor (NF)-kB p65 phosphorylation was attenuated by sSiglec-9, and chemical blockade of the NF-kB pathway reduced M1 marker expression in RAW264.7 cells.
In this study, we have demonstrated the therapeutic effects of sSiglec-9 in a murine CIA model. The mechanism underlying these effects involves the suppression of M1 proinflammatory macrophages by inhibiting the NF-kB pathway. sSiglec-9 may provide a novel therapeutic option for patients with rheumatoid arthritis refractory to currently available drugs.
本研究旨在评估可溶性唾液酸结合免疫球蛋白样凝集素（sSiglec）-9对小鼠胶原诱导性关节炎（CIA）模型以及类风湿关节炎患者来源的小鼠巨噬细胞（RAW264.7细胞和腹腔巨噬细胞）和成纤维样滑膜细胞（FLS）单层培养物中关节炎症和破坏的影响。
用II型胶原免疫DBA/1J小鼠。使用生理关节炎评分、组织学分析、血清肿瘤坏死因子（TNF）-α浓度以及叉头框P3（Foxp3）阳性调节性T（Treg）细胞比例来评估sSiglec-9的作用。体内生物荧光成像用于评估sSiglec-9的分布。检测巨噬细胞中M1（TNF-α、白细胞介素[IL]-6和诱导型一氧化氮合酶）和M2（CD206、精氨酸酶-1和IL-10）巨噬细胞标志物水平以及细胞内信号分子的磷酸化情况，并检测FLS中基质金属蛋白酶（MMP）-1、MMP-3和MMP-13的水平。
sSiglec-9显著抑制关节炎的临床和组织学发病率及严重程度。体内Foxp3阳性Treg细胞比例显著改善，血清TNF-α浓度降低。虽然sSiglec-9降低了巨噬细胞中M1标志物的表达，但它不影响FLS中M2标志物和MMP的表达。sSiglec-9减弱了核因子（NF）-κB p65的磷酸化，并且NF-κB途径的化学阻断降低了RAW264.7细胞中M1标志物的表达。
在本研究中，我们证明了sSiglec-9在小鼠CIA模型中的治疗作用。这些作用的潜在机制涉及通过抑制NF-κB途径来抑制M
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