The impact of spleen tyrosine kinase (Syk) signaling might be prominent in lupus because (i) Syk is a shared downstream signaling molecule among circulating immune complex, LPS, and (1→3)-β-D-glucan (BG), and (ii) all of these factors are detectable in the serum of Fc gamma receptor IIb-deficient (FcgRIIb^−/−) mice with sepsis. As a proof of concept study, we activated macrophages with BG combined with LPS (BG + LPS). We found that BG + LPS predominantly upregulated Syk expression and proinflammatory cytokines in FcgRIIb^−/− macrophages compared with wild-type (WT) macrophages. Syk inhibition downregulated several inflammatory pathways in FcgRIIb^−/− macrophages activated with BG + LPS, as determined by RNA sequencing analysis, suggesting the potential anti-inflammatory impact of Syk inhibitors in lupus. Indeed, administration of a Syk inhibitor prior to cecal ligation and puncture (CLP) sepsis in FcgRIIb^−/− mice reduced baseline lupus-induced proinflammatory cytokines and attenuated sepsis severity as evaluated by mortality, organ injury, serum LPS, and post-sepsis serum cytokines. In conclusion, it was easier to induce Syk expression in FcgRIIb^−/− macrophages than in WT macrophages. This might be because of the loss of inhibitory signaling, which might be responsible for prominent Syk abundance in the spleens of 40-week-old FcgRIIb^−/− mice and the potent effect of Syk inhibitor in lupus mice compared with WT.
J Innate Immun

中文翻译：

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Syk 抑制剂可减轻 FcgRIIb 缺陷型狼疮小鼠模型中的多种微生物败血症，以及狼疮特征对败血症的影响。


脾酪氨酸激酶 (Syk) 信号传导的影响在狼疮中可能很突出，因为 (i) Syk 是循环免疫复合物、LPS 和 (1→3)-β-D-葡聚糖 (BG) 之间共享的下游信号传导分子，并且(ii) 所有这些因素均可在患有败血症的 Fc γ 受体 IIb 缺陷 (FcgRIIb ^−/− ) 小鼠的血清中检测到。作为概念验证研究，我们用 BG 结合 LPS (BG + LPS) 激活巨噬细胞。我们发现，与野生型（WT）巨噬细胞相比，BG + LPS 主要上调 FcgRIIb ^-/−巨噬细胞中的 Syk 表达和促炎细胞因子。通过 RNA 测序分析确定，Syk 抑制下调了由 BG + LPS 激活的 FcgRIIb ^−/−巨噬细胞中的多种炎症途径，这表明 Syk 抑制剂在狼疮中具有潜在的抗炎作用。事实上，根据死亡率、器官损伤、血清 LPS 和脓毒症后血清的评估，在 FcgRIIb ^−/−小鼠盲肠结扎穿刺 (CLP) 脓毒症之前给予 Syk 抑制剂可减少狼疮诱导的促炎细胞因子的基线，并减轻脓毒症的严重程度细胞因子。总之，在 FcgRIIb ^−/−巨噬细胞中诱导 Syk 表达比在 WT 巨噬细胞中更容易。这可能是因为抑制信号传导的丧失，这可能是 40 周龄 FcgRIIb ^−/−小鼠脾脏中 Syk 丰度显着的原因，以及与 WT 相比，Syk 抑制剂在狼疮小鼠中的有效作用。
 天然免疫杂志