Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling
Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling
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DOI：
10.1016/j.ebiom.2019.06.040
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发表时间：
2019-07-01
期刊：
影响因子：
11.1
通讯作者：
Perkins, Douglas J.
中科院分区：
文献类型：
--
作者：
Achieng, Angela O.;Guyah, Bernard;Perkins, Douglas J.
背景资料：白细胞相关免疫球蛋白样受体-1（LAIR 1）是一种跨膜抑制性受体，影响炎症性疾病的易感性。我们最近对肯尼亚儿童严重疟疾贫血（SMA）发病机制的研究发现，与LAIR 1转录物减少相关的新型LAIR 1遗传变异增加了SMA的纵向风险和全因死亡率。方法：为了表征在严重疟疾中LAIR 1信号传导改变的分子机制，我们测定了LAIR 1转录物和蛋白质，sLAIR 1，sLAIR 2，和补体成分1q（C1q）在儿童疟疾贫血，随后通过一系列的体外实验调查LAIR1信号cascades.Findings：肯尼亚儿童SMA有较高的循环水平的可溶性LAIR1（sLAIR1）相对于非SMA（1.69倍P <0.0001）。LAIR 1拮抗剂sLAIR 2在SMA患儿的循环中也升高（1.59倍变化，P <0.0001）。sLAIR 1和sLAIR 2之间呈正相关（rho = 0.741，P <0.0001）。相反，补体成分1q（C1q）（LAIR 1天然配体）的循环水平在SMA中较低（-1.21倍P =.048）。这些体内研究结果表明，SMA中膜结合LAIR 1表达减少与sLAIR 1、sLAIR 2（拮抗剂）产生增加和C1q（激动剂）可用性有限相关。由于SMA中LAIR 1转录物的减少与单核细胞对疟原虫色素（PfHz）的获得增加有关（P =.028），我们探讨了白细胞内PfHz的获得、LAIR 1表达和随后对来自未患疟疾的供体的培养PBMC中白细胞信号传导的影响之间的关系，这些供体用生理浓度的PfHz（10 μ g/mL）刺激。PfHz的吞噬作用以时间依赖的方式降低LAIR 1的转录和蛋白表达（P <0.050），并通过降低LAIR 1（P <0.0001）和含SH2结构域的磷酸酶-1（SHP-1）（P <0.001）的磷酸化来抑制LAIR 1信号传导。这一过程与NF-κ B B活化有关（P <.0001）和IL-6、IL-1 β和TNF-α的产生增加（所有P <.0001）。解释：总的来说，这些发现表明SMA的特征在于LAIR 1跨膜表达减少、C1q减少以及sLAIR 1和sLAIR 2的产生增加，分子事件，可以促进细胞因子的产生增加，有助于SMA的发病机制。这些研究对于发现免疫检查点非常重要，这些免疫检查点可能是未来免疫治疗的目标，以改善疾病的结果。(C)2019由Elsevier B.V.出版
Background: Leukocyte-associated immunoglobulin like receptor-1 (LAIR1) is a transmembrane inhibitory receptor that influences susceptibility to amyriad of inflammatory diseases. Our recent investigations of severe malarial anaemia (SMA) pathogenesis in Kenyan children discovered that novel LAIR1 genetic variants which were associated with decreased LAIR1 transcripts enhanced the longitudinal risk of SMA and all-cause mortality.Methods: To characterize themolecular mechanism(s) responsible for altered LAIR1 signalling in severe malaria, we determined LAIR1 transcripts and protein, sLAIR1, sLAIR2, and complement component 1q (C1q) in children with malarial anaemia, followed by a series of in vitro experiments investigating the LAIR1 signalling cascade.Findings: Kenyan children with SMA had elevated circulating levels of soluble LAIR1 (sLAIR1) relative to non-SMA (1.69-fold P < .0001). The LAIR1 antagonist, sLAIR2, was also elevated in the circulation of children with SMA (1.59 fold-change, P < .0001). There was a positive correlation between sLAIR1 and sLAIR2 (rho = 0.741, P < .0001). Conversely, circulating levels of complement component 1q (C1q), a LAIR1 natural ligand, were lower in SMA (-1.21-fold P =.048). These in vivo findings suggest that reduced membrane-bound LAIR1 expression in SMA is associatedwith elevated production of sLAIR1, sLAIR2 (antagonist), and limited C1q (agonist) availability. Since reduced LAIR1 transcripts in SMA were associated with increased acquisition of haemozoin (PfHz) by monocytes (P =.028), we explored the relationship between acquisition of intraleukocytic PfHz, LAIR1 expression, and subsequent impacts on leukocyte signalling in cultured PBMCs from malaria-naive donors stimulated with physiological concentrations of PfHz (10 mu g/mL). Phagocytosis of PfHz reduced LAIR1 transcript and protein expression in a time-dependentmanner (P < .050), and inhibited LAIR1 signalling through decreased phosphorylation of LAIR1 (P < .0001) and SH2-domain containing phosphatase-1 (SHP-1) (P < .001). This process was associated with NF-kappa B activation (P < .0001) and enhanced production of IL-6, IL-1 beta, and TNF-alpha (all P < .0001).Interpretation: Collectively, these findings demonstrate that SMA is characterized by reduced LAIR1 transmembrane expression, reduced C1q, and enhanced production of sLAIR1 and sLAIR2, molecular eventswhich can promote enhanced production of cytokines that contribute to the pathogenesis of SMA. These investigations are important for discovering immune checkpoints that could be future targets of immunotherapy to improve disease outcomes. (C) 2019 Published by Elsevier B.V.