Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.
Natural IgM Switches the Function of Lipopolysaccharide-Activated Murine Bone Marrow-Derived Dendritic Cells to a Regulatory Dendritic Cell That Suppresses Innate Inflammation.
复制标题
DOI：
10.4049/jimmunol.1500052
复制
发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Okusa MD
中科院分区：
文献类型：
--
作者：
Lobo PI;Schlegel KH;Bajwa A;Huang L;Kurmaeva E;Wang B;Ye H;Tedder TF;Kinsey GR;Okusa MD
我们之前已经证明，多克隆天然IgM通过抑制再灌注炎症反应来保护小鼠免受肾IRI。我们假设一种潜在的机制涉及IgM对树突状细胞的调节，因为我们观察到IgM与脾DC的高结合。为了验证这一假设，我们在LPS激活之前用多克隆小鼠或人IgM预处理BMDC，并证明0.5 × 106 IgM/LPS预处理BMDC，在肾缺血前24小时注射到WT-B6小鼠体内，可以保护小鼠不发生肾IRI。我们发现，脂多糖激活的BMDC向调节性表型的转变需要通过IgM结合非凋亡BMDC受体介导的BMDC功能调节。调节性BMDC需要IL-10和PD1以及下调CD40和p65NF-κB磷酸化来保护肾IRI。在静脉注射IgM/LPS预处理的BMDC或使用IL-10ko BMDC之前阻断PD1配体结合位点不能诱导保护。同样，IgM/LPS预处理的BMDC通过增加CD40表达和p65NF-κB磷酸化而变得无保护作用。IgM/LPS调控BMDC如何抑制体内缺血诱导的先天炎症仍有待确定。然而，我们发现这种抑制依赖于宿主体内的其他调节机制，即CD25+ T细胞、B细胞、IL10和循环IgM。肾IRI前后脾脏Foxp3+ Tregs均未见升高。总的来说，这些发现表明，尽管存在通常诱导BMDC成熟的LPS，但天然IgM抗白细胞抗体可以将BMDC转换为调节性表型。
We have previously shown that polyclonal natural IgM protects mice from renal IRI by inhibiting the reperfusion inflammatory response. We hypothesized that a potential mechanism involved IgM modulation of dendritic cells as we observed high IgM binding to splenic DC. To test this hypothesis, we pre-treated BMDC with polyclonal murine or human IgM prior to LPS activation and demonstrate that 0.5 × 106 IgM/LPS pretreated BMDC, when injected into WT-B6 mice, 24 hours before renal ischemia, protect mice from developing renal IRI. We show that this switching of LPS activated BMDC to a regulatory phenotype requires modulation of BMDC function that is mediated by IgM binding to non-apoptotic BMDC receptors. Regulatory BMDC require IL-10 and PD1 as well as downregulation of CD40 and p65NF-κB phosphorylation to protect in renal IRI. Blocking the PD1 ligand binding site just before intravenous injection of IgM/LPS pretreated BMDC or using IL-10ko BMDC fails to induce protection. Similarly, IgM/LPS pretreated BMDC are rendered non-protective by increasing CD40 expression and phosphorylation of p65NF-κB. How IgM/LPS regulatory BMDC suppress in-vivo ischemia induced innate inflammation remains to be determined. However, we show that suppression is dependent on other in-vivo regulatory mechanisms in the host i.e. CD25+ T cells, B cells, IL10 and circulating IgM. There was no increase in Foxp3+ Tregs in the spleen either before or after renal IRI. Collectively, these findings show that natural IgM anti-leucocyte antibodies can switch BMDC to a regulatory phenotype despite the presence of LPS that ordinarily induces BMDC maturation.