Inhibition of store-operated calcium entry in microglia by helminth factors: implications for immune suppression in neurocysticercosis.
Inhibition of store-operated calcium entry in microglia by helminth factors: implications for immune suppression in neurocysticercosis.
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DOI：
10.1186/s12974-014-0210-7
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发表时间：
2014-12-24
影响因子：
9.3
通讯作者：
Mishra BB
中科院分区：
文献类型：
--
作者：
Sun Y;Chauhan A;Sukumaran P;Sharma J;Singh BB;Mishra BB
神经囊虫病（NCC）是一种由猪带绦虫引起的中枢神经系统疾病。在出现症状期之前，感染表现为漫长的无症状期，通常持续3至5年。症状的严重程度被认为与退化的寄生虫引起的炎症反应的强度有关。相比之下，无症状期显示没有脑炎症，这可能是由于活寄生虫的免疫抑制作用。然而，参与抑制炎症的宿主因子和/或途径在很大程度上仍然未知。最近，我们在NCC动物模型中，将一种相关的寄生虫Mesocestoides corti注入小鼠脑内，报道toll样受体（TLR）相关信号通路参与炎症反应的发展。由于小胶质细胞在中枢神经系统中形成最初的先天免疫反应，我们假设tlr诱导的小胶质细胞炎症通路的负调控可能是NCC中蠕虫相关的一种新的免疫抑制机制。在这里，我们报道了来自中皮甾体皮质的蠕虫可溶性因子（HSFs）抑制TLR结扎诱导的初级小胶质细胞炎症细胞因子的产生。这与tlr引发的核因子κB (NF-κB) p65亚基磷酸化和乙酰化上调，以及JNK和ERK1/2磷酸化的抑制有关。由于存储操作Ca2+进入（SOCE）引起的Ca2+内流与下游信号传导的诱导有关，我们测试了hsf对激动剂诱导的Ca2+内流和特异性Ca2+通道激活的抑制作用。我们发现，HSFs通过阻断内质网储存释放和SOCE，消除了脂多糖（LPS）或信号素（Tg）诱导的细胞内Ca2+积累的增加。此外，电生理记录表明，hsf介导的抑制LPS或tg诱导的SOCE电流通过质膜上的TRPC1和ORAI1 Ca2+通道。这与质膜上TRPC1-STIM1和ORAI1-STIM1聚集性的减少有关，这是维持Ca2+通过这些通道进入所必需的。抑制小胶质细胞中TRPC1和ORAI1 Ca2+通道介导的NF-κB和MAPK通路的激活可能是蠕虫诱导的一种新的免疫抑制机制，可以控制中枢神经系统炎症反应的启动。
Neurocysticercosis (NCC) is a disease of the central nervous system (CNS) caused by the cestode Taenia solium. The infection exhibits a long asymptomatic phase, typically lasting 3 to 5 years, before the onset of the symptomatic phase. The severity of the symptoms is thought to be associated with the intensity of the inflammatory response elicited by the degenerating parasite. In contrast, the asymptomatic phase shows an absence of brain inflammation, which is presumably due to immunosuppressive effects of the live parasites. However, the host factors and/or pathways involved in inhibiting inflammation remain largely unknown. Recently, using an animal model of NCC in which mice were intracranially inoculated with a related helminth parasite, Mesocestoides corti, we reported that Toll-like receptor (TLR)-associated signaling contributes to the development of the inflammatory response. As microglia shape the initial innate immune response in the CNS, we hypothesized that the negative regulation of a TLR-induced inflammatory pathway in microglia may be a novel helminth-associated immunosuppressive mechanism in NCC. Here we report that helminth soluble factors (HSFs) from Mesocestoides corti inhibited TLR ligation-induced production of inflammatory cytokines in primary microglia. This was correlated with an inhibition of TLR-initiated upregulation of both phosphorylation and acetylation of the nuclear factor κB (NF-κB) p65 subunit, as well as phosphorylation of JNK and ERK1/2. As Ca2+ influx due to store-operated Ca2+ entry (SOCE) has been implicated in induction of downstream signaling, we tested the inhibitory effect of HSFs on agonist-induced Ca2+ influx and specific Ca2+ channel activation. We discovered that HSFs abolished the lipopolysaccharide (LPS)- or thapsigargin (Tg)-induced increase in intracellular Ca2+ accumulation by blocking the ER store release and SOCE. Moreover, electrophysiological recordings demonstrated HSF-mediated inhibition of LPS- or Tg-induced SOCE currents through both TRPC1 and ORAI1 Ca2+ channels on plasma membrane. This was correlated with a decrease in the TRPC1-STIM1 and ORAI1-STIM1 clustering at the plasma membrane that is essential for sustained Ca2+ entry through these channels. Inhibition of TRPC1 and ORAI1 Ca2+ channel-mediated activation of NF-κB and MAPK pathways in microglia is likely a novel helminth-induced immunosuppressive mechanism that controls initiation of inflammatory response in the CNS.
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影响因子：
1.5
作者：
Hewitson, James P.;Grainger, John R.;Maizels, Rick M.
通讯作者：
Maizels, Rick M.
影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
神经囊肿中的Tegument糖缀合物的差异释放和吞噬作用：对免疫逃避策略的影响。
影响因子：
3.8
作者：
Alvarez JI;Rivera J;Teale JM
通讯作者：
Teale JM
影响因子：
1.3
作者：
CORREA, D;DALMA, D;FLISSER, A
通讯作者：
FLISSER, A
影响因子：
1.5
作者：
Haslam, SM;Restrepo, BI;Dell, A
通讯作者：
Dell, A