C-type lectin receptor Dectin3 deficiency balances the accumulation and function of FoxO1-mediated LOX-1(+) M-MDSCs in relieving lupus-like symptoms.
C-type lectin receptor Dectin3 deficiency balances the accumulation and function of FoxO1-mediated LOX-1(+) M-MDSCs in relieving lupus-like symptoms.
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C型凝集素受体Dectin3缺乏平衡FoxO1介导的LOX-1（）M-MDSC的积累和功能，缓解狼疮样症状
DOI：
10.1038/s41419-021-04052-5
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发表时间：
2021-09-03
影响因子：
9
通讯作者：
Hou Y
中科院分区：
文献类型：
--
作者：
Li D;Lu L;Kong W;Xia X;Pan Y;Li J;Wang J;Wang T;Liang J;Dou H;Hou Y
近年来的研究表明，Toll样受体（TLR）和C型凝集素受体（CLRs）可作为模式识别受体的信号分子，在自身免疫性疾病的发病机制中起着关键作用。系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病。以往的研究主要集中在TLRs在SLE发生发展中的潜在作用，而CLRs在SLE发生发展中的作用尚不清楚。我们前期的研究表明炎症介导的髓源性抑制细胞（MDSCs）包括粒细胞（G-MDSCs）和单核细胞（M-MDSCs）的聚集参与了狼疮的发病机制。缺乏Card 9（CLRs的下游分子）的小鼠通过促进MDSC的扩增而更容易患结肠炎相关癌症。CLRs的异常激活是否调节MDSC的扩增以参与狼疮的发病机制仍然未知。在本研究中，CLRs的表达检测在SLE患者和小鼠模型，揭示Dectin 3的表达与SLEDAI呈正相关。Dectin 3缺陷通过调节MDSC的扩增和功能延缓狼疮样疾病。机制分析显示Dectin 3缺陷促进FoxO 1介导的MDSCs凋亡。Syk-Akt 1介导的FoxO 1核转移在Dectin 3缺陷的MDSC中增加。值得注意的是，M-MDSC的积累主要在Dectin 3 −/−狼疮小鼠中减少，FoxO 1的核转移与M-MDSC上LOX-1的表达呈负相关。Dectin 3 −/−小鼠中FoxO 1表达的沉默促进了LOX-1+ M-MDSC的体内扩增，LOX-1+ M-MDSC增加了Th 17细胞的分化。SLE患者M-MDSC上LOX-1表达和MDSC上Dectin 3表达均增加。提示LOX-1+ M-MDSCs的表达增加与SLE病情加重有关，可能是SLE治疗的潜在靶细胞。
Recent studies indicate that Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) can function as the signal of pattern recognition receptors, which play a pivotal role in the pathogenesis of the autoimmune disease. Systemic lupus erythematosus (SLE) is a classic autoimmune disease. Previous reports mainly focused on the potential role of TLRs in regulating the development of SLE, but little is known about the role of CLRs in the progression of SLE. Our previous studies showed that the inflammation-mediated accumulation of myeloid-derived suppressor cells (MDSCs) including granulocytic (G-MDSCs) and monocytic (M-MDSCs) participated in the pathogenesis of lupus. Mice deficient in Card9 (the downstream molecule of CLRs) were more susceptible to colitis-associated cancer via promoting the expansion of MDSCs. Whether the abnormal activation of CLRs regulates the expansion of MDSCs to participate in the pathogenesis of lupus remains unknown. In the present study, the expressions of CLRs were examined in both SLE patients and mouse models, revealing the expression of Dectin3 was positively correlated with SLEDAI. Dectin3 deficiency retarded the lupus-like disease by regulating the expansion and function of MDSCs. The mechanistic analysis revealed that Dectin3 deficiency promoted FoxO1-mediated apoptosis of MDSCs. Syk-Akt1-mediated nuclear transfer of FoxO1 increased in Dectin3-deficient MDSCs. Notedly, the accumulation of M-MDSCs mainly decreased in Dectin3−/− lupus mice, and the nuclear transfer of FoxO1 negatively correlated with the expression of LOX-1 on M-MDSCs. The silencing of FoxO1 expression in Dectin3−/− mice promoted the expansion of LOX-1+ M-MDSCs in vivo, and LOX-1+ M-MDSCs increased the differentiation of Th17 cells. Both LOX-1 expression on M-MDSCs and Dectin3 expression on MDSCs increased in patients with SLE. These data indicated that increased LOX-1+ M-MDSCs were related to the exacerbation of SLE development and might be potential target cells for the treatment of SLE.
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