S1P1 Contributes to Endotoxin-enhanced B-Cell Functions Involved in Hypersensitivity Pneumonitis
S1P1 Contributes to Endotoxin-enhanced B-Cell Functions Involved in Hypersensitivity Pneumonitis
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DOI：
10.1165/rcmb.2019-0339oc
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发表时间：
2020-08-01
影响因子：
6.4
通讯作者：
Marsolais, David
中科院分区：
文献类型：
--
作者：
Huppe, Carole-Ann;Blais-Lecours, Pascale;Marsolais, David
在一部分过敏性肺炎患者中，维持炎症的生物和环境因素定义不清，导致没有有效的治疗选择。在职业环境中发现的生物气溶胶是复杂的，通常包括Toll样受体配体，如内毒素。然而，Toll样受体配体如何促进过敏性肺炎的持续存在，仍然知之甚少。在先前的研究中，我们发现S1 P（1）（鞘氨醇-1-磷酸受体1）激动剂阻止了肺中抗原驱动的B细胞反应的重新激活。在此，我们评估了内毒素对既存过敏性肺炎中B细胞活化的影响以及S1 P（1）在这一现象中的作用。在体内研究了内毒素对预先建立的过敏性肺炎的影响。使用S1 P（1）-eGFP敲入小鼠在疾病过程中追踪B细胞上的S1 P（1）水平，并使用药理学工具评估S1 P1对B细胞功能的作用。实验性过敏性肺炎B细胞上有S1 P（1）表达。内毒素暴露增强了实验性过敏性肺炎小鼠BAL中中性粒细胞的积聚。这与BAL中淋巴细胞上CD 69细胞表面表达增强有关。在分离的B细胞中，内毒素增加了细胞表面共刺激分子和CD 69的水平，这一点可被S1 P（1）激动剂阻止。S1 P（1）调节剂也降低了B细胞产生TNF的能力，以及它们在体外触发T细胞协同作用的能力。S1 P（1）配体直接抑制内毒素诱导的B细胞活化。
In a proportion of patients with hypersensitivity pneumonitis, the biological and environmental factors that sustain inflammation are ill defined, resulting in no effective treatment option. Bioaerosols found in occupational settings are complex and often include Toll-like receptor ligands, such as endotoxins. How Toll-like receptor ligands contribute to the persistence of hypersensitivity pneumonitis, however, remains poorly understood. In a previous study, we found that an S1P(1) (sphingosine-1-phosphate receptor 1) agonist prevented the reactivation of antigen-driven B-cell responses in the lung. Here, we assessed the impact of endotoxins on B-cell activation in preexisting hypersensitivity pneumonitis and the role of S1P(1) in this phenomenon. The impact of endotoxins on pre-established hypersensitivity pneumonitis was studied in vivo. S1P(1) levels were tracked on B cells in the course of the disease using S1P(1)-eGFP knockin mice, and the role of S1P1 on B-cell functions was assessed using pharmacological tools. S1P(1) was found on B cells in experimental hypersensitivity pneumonitis. Endotoxin exposure enhanced neutrophil accumulation in the BAL of mice with experimental hypersensitivity pneumonitis. This was associated with enhanced CD69 cell-surface expression on lymphocytes in the BAL. In isolated B cells, endotoxins increased cell-surface levels of costimulatory molecules and CD69, which was prevented by an S1P(1) agonist. S1P(1) modulators also reduced TNF production by B cells and their capacity to trigger T-cell cooperation ex vivo. An S1P(1) ligand directly inhibited endotoxin-induced B-cell activation.