Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China.
Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
Front Immunol. 2022 Jul 5;13:913901. doi: 10.3389/fimmu.2022.913901. eCollection 2022.
Osteoarthritis (OA) is a deteriorating disease of cartilage tissues mainly characterized as low-grade inflammation of the joint. Innate immune molecule surfactant protein D (SP-D) is a member of collectin family of collagenous Ca-dependent defense lectins and plays a vital role in the inflammatory and innate immune responses. The present study investigated the SP-D-mediated innate/inflammatory bioregulation in OA and explored the underlying molecular mechanism. Transcriptome analysis revealed that SP-D regulated genes were strongly enriched in the inflammatory response, immune response, cellular response to lipopolysaccharide (LPS), PI3K-Akt signaling, Toll-like receptor (TLR) signaling, and extracellular matrix (ECM)-receptor interaction pathways. Knockdown of the SP-D gene by the recombinant adeno-associated virus promoted the macrophage specific markers of CD68, F4/80 and TLR4 in the articular cartilage . SP-D alleviated the infiltration of synovial macrophages and neutrophils, and inhibited TLR4, TNF-α and the phosphorylation of PI3K, Akt and NF-κB p65 in cartilage. SP-D suppressed cartilage degeneration, inflammatory and immune responses in the rat OA model, whilst TAK-242 strengthened this improvement. In conditions, SP-D pre-treatment inhibited LPS-induced overproduction of inflammation-correlated cytokines such as IL-1β and TNF-α, and suppressed the overexpression of TLR4, MD-2 and NLRP3. SP-D prevented the LPS-induced degradation of ECM by down-regulating MMP-13 and up-regulating collagen II. Blocking of TLR4 by TAK-242 further enhanced these manifestations. We also demonstrated that SP-D binds to the TLR4/MD-2 complex to suppress TLR4-mediated PI3K/Akt and NF-κB signaling activation in chondrocytes. Taken together, these findings indicate that SP-D has chondroprotective properties dependent on TLR4-mediated PI3K/Akt and NF-κB signaling and that SP-D has an optimal bioregulatory effect on the inflammatory and innate responses in OA.
骨关节炎（OA）是一种软骨组织恶化疾病，主要表现为关节低度炎症。先天免疫分子表面活性剂蛋白 D（SP-D）是富含胶原蛋白的 Ca 依赖性防御凝集素的集合素家族的成员，在炎症和先天免疫反应中发挥重要作用。本研究探讨了 SP-D 在 OA 中的固有/炎症性生物调节作用，并探索了其潜在的分子机制。转录组分析表明，SP-D 调节的基因在炎症反应、免疫反应、细胞对脂多糖（LPS）的反应、PI3K-Akt 信号转导、Toll 样受体（TLR）信号转导和细胞外基质（ECM）-受体相互作用途径中强烈富集。重组腺相关病毒敲低 SP-D 基因促进了软骨中巨噬细胞特异性标志物 CD68、F4/80 和 TLR4 的表达。SP-D 减轻了滑膜巨噬细胞和中性粒细胞的浸润，并抑制了软骨中的 TLR4、TNF-α 和 PI3K、Akt 和 NF-κB p65 的磷酸化。SP-D 抑制了大鼠 OA 模型中的软骨退变、炎症和免疫反应，而 TAK-242 则加强了这种改善。在 LPS 刺激条件下，SP-D 预处理抑制了炎症相关细胞因子如 IL-1β和 TNF-α的过度产生，并抑制了 TLR4、MD-2 和 NLRP3 的过度表达。SP-D 通过下调 MMP-13 和上调胶原 II 来防止 LPS 诱导的 ECM 降解。TAK-242 阻断 TLR4 进一步增强了这些表现。我们还证明 SP-D 与 TLR4/MD-2 复合物结合，抑制软骨细胞中 TLR4 介导的 PI3K/Akt 和 NF-κB 信号通路的激活。综上所述，这些发现表明 SP-D 具有依赖 TLR4 介导的 PI3K/Akt 和 NF-κB 信号的软骨保护特性，并且 SP-D 对 OA 中的炎症和先天反应具有最佳的生物调节作用。
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