Siglec-G Deficiency Ameliorates Hyper-Inflammation and Immune Collapse in Sepsis via Regulating Src Activation
Siglec-G Deficiency Ameliorates Hyper-Inflammation and Immune Collapse in Sepsis via Regulating Src Activation
复制标题
Siglec-G 缺乏通过调节 Src 激活改善脓毒症中的过度炎症和免疫崩溃
DOI：
10.3389/fimmu.2019.02575
复制
发表时间：
2019-11-07
影响因子：
7.3
通讯作者：
Luo, Yan
中科院分区：
文献类型：
--
作者：
Li, Wenqian;Li, Yinjiao;Luo, Yan
巨噬细胞/单核细胞在急性期的过度炎症和免疫抑制期的低炎症导致多器官衰竭综合征和脓毒症的免疫崩溃，其中Toll样受体（TLR）触发的炎症反应起主要作用。在这里，我们报道了Siglecg缺乏症在急性和免疫抑制阶段在体内和体外减弱TLR 4触发的促炎细胞因子产生并增加抗炎细胞因子[白细胞介素-10 [IL-10]]的产生。Siglecg缺陷还保护小鼠免受脂多糖（LPS）诱导的脓毒症，肺部炎症较少，脾脏组织破坏较少。Siglec-G通过基于免疫受体酪氨酸的抑制基序（ITIM）结构域募集和激活含酪氨酸磷酸酶Src同源区2结构域的磷酸酶-1（SHP 1），抑制原癌基因酪氨酸蛋白激酶Src（Src）激活。Src可抑制TLR 4诱导的炎性细胞因子，促进抗炎细胞因子IL-10的产生。机械研究表明Src可以与STAT 3相互作用并磷酸化STAT 3。Src还可通过激活GSK 3 β促进HIF 1 α的降解。我们的研究表明，Siglec-G协调TLR诱导的炎症，这表明阻断Siglec-G或激活Src可能是治疗急性和慢性炎症性疾病的一种有前途的策略。
Hyper-inflammation during acute phase and sequential hypo-inflammation during immunosuppressive phase in macrophages/monocytes lead to multiorgan failure syndrome and immune collapse of sepsis, in which toll-like receptor (TLR)-triggered inflammatory responses play a major role. Here, we reported that Siglecg deficiency attenuated TLR4-triggered pro-inflammatory cytokine production and increased anti-inflammatory cytokine [interleukin-10 [IL-10]] production in vivo and in vitro at both acute and immunosuppressive phases. Siglecg deficiency also protected mice from lipopolysaccharide (LPS)-induced sepsis with less inflammation in the lung and less tissue destruction in the spleen. Siglec-G inhibited proto-oncogene tyrosine-protein kinase Src (Src) activation via recruiting and activating tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP1) through immunoreceptor tyrosine-based inhibitory motif (ITIM) domain. Src could inhibit TLR4-induced inflammatory cytokines and promote anti-inflammatory cytokine IL-10. Mechanical investigation showed that Src could interact with and phosphorylate STAT3. Src could also promote HIF1α degradation through activating GSK3β. Our study reveals that Siglec-G orchestrates TLR-induced inflammation, which outlines that blocking Siglec-G or activating Src may be a promising strategy for both acute and chronic inflammatory diseases.