LPS膿毒癥模型SLAMF7 調節(jié)巨噬細胞炎癥反應

中文摘要：

膿毒癥中發(fā)生的不受控制的炎癥會導致多器官損傷和休克，從而導致膿毒癥患者死亡。然而，限制過度炎癥的調節(jié)機制仍然難以捉摸。在這里，我們確定了一種稱為信號淋巴細胞活化分子家族 7 （SLAMF7） 的 Ig 樣受體是膿毒癥期間炎癥的關鍵抑制因子。我們發(fā)現(xiàn)膿毒癥患者和膿毒癥小鼠單核細胞/巨噬細胞上 SLAMF7 的表達顯著升高。SLAMF7 通過與含有 Src 同源 2 的肌醇-5′-磷酸酶 1 （SHIP1） 合作，減弱巨噬細胞中 TLR 依賴性 MAPK 和 NF-κB 信號激活。此外，SLAMF7 與 SHIP1 和 TNF 受體相關因子 6 （TRAF6） 相互作用，抑制 TRAF6 的 K63 泛素化。此外，我們發(fā)現(xiàn) SLAMF7 胞內結構域和 SHIP1 磷酸酶結構域內的酪氨酸磷酸化位點對于 SLAMF7、SHIP1 和 TRAF6 與 SLAMF7 介導的細胞因子產生的調節(jié)之間的相互作用是必需的。最后，我們證明 SLAMF7 通過下調巨噬細胞促炎細胞因子和抑制炎癥誘導的器官損傷來預防致命的膿毒癥和內毒素血癥。綜上所述，我們的研究結果揭示了 SLAMF7 在多種微生物膿毒癥中的負調節(jié)作用，從而為膿毒癥的治療提供了視野。

英文摘要：

Uncontrolled inflammation occurred in sepsis results in multiple organ injuries and shock, which contributes to the death of patients with sepsis. However, the regulatory mechanisms that restrict excessive inflammation are still elusive. Here, we identified an Ig-like receptor called signaling lymphocyte activation molecular family 7 (SLAMF7) as a key suppressor of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes/macrophages was significantly elevated in patients with sepsis and in septic mice. SLAMF7 attenuated TLR-dependent MAPK and NF-κB signaling activation in macrophages by cooperating with Src homology 2–containing inositol-5′?phosphatase 1 (SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor–associated factor 6 (TRAF6) to inhibit K63 ubiquitination of TRAF6. In addition, we found that tyrosine phosphorylation sites within the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 were indispensable for the interaction between SLAMF7, SHIP1, and TRAF6 and SLAMF7-mediated modulation of cytokine production. Finally, we demonstrated that SLAMF7 protected against lethal sepsis and endotoxemia by downregulating macrophage proinflammatory cytokines and suppressing inflammation-induced organ damage. Taken together, our findings reveal a negative regulatory role of SLAMF7 in polymicrobial sepsis, thus providing sights into the treatment of sepsis.

論文信息：

論文題目： HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis

期刊名稱：J Clin Invest.  

時間期卷：2023;133(6):e150224

在線時間：2023年2月7日

DOI：doi.org/10.1172/JCI150224.

產品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點科技）

Clodronate Liposomes氯膦酸鹽脂質體助力LPS膿毒癥模型SLAMF7 調節(jié)巨噬細胞炎癥反應巨噬細胞研究，荷蘭Liposoma巨噬細胞清除劑Clodronate Liposomes見刊于JCI：

LPS膿毒癥模型SLAMF7 調節(jié)巨噬細胞炎癥反應

Liposoma巨噬細胞清除劑ClodronateLiposomes氯膦酸二鈉脂質體的材料和方法：

Macrophage depletion

Liposomes, composed of phospholipid bilayers and containing dichloromethylene diphosphonate (clodronate liposomes), or PBS (control liposomes) were purchased from Liposoma BV. A total of 100 μL clodronate-containing liposome suspension was injected i.p. into WT and SLAMF7-KO mice as previously described . Macrophages were depleted in the peritoneal lavage for up to 1 week after clodronate liposomes injection.

巨噬細胞清除/耗竭

脂質體由磷脂雙層組成，含有二氯亞甲基二膦酸鹽（氯膦酸鹽脂質體）或 PBS（對照脂質體）購自荷蘭Liposoma BV。如前所述，將總共 100 μL 含氯膦酸鹽的脂質體懸浮液經(jīng)腹腔注射到 WT 和 SLAMF7-KO 小鼠中。在注射氯膦酸鹽脂質體后長達 1 周，巨噬細胞在腹腔灌洗液中耗盡。