Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a)
Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a)
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DOI：
10.1038/gene.2008.23
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发表时间：
2008-06-01
影响因子：
5
通讯作者：
Fierer, J.
中科院分区：
文献类型：
--
作者：
Jimenez-A, M. del Pilar;Viriyakosol, S.;Fierer, J.
Coccidioides posadasii 小球通过 TLR-2 和 Dectin-1 刺激巨噬细胞产生细胞因子。我们使用福尔马林灭活的小球和从小球纯化的 1,3-β-葡聚糖来刺激易感 (C57BL/6) 和耐药 (DBA/2) 小鼠品系引发的腹膜巨噬细胞和骨髓树突细胞 (mDC)。 DBA/2 巨噬细胞比 C57BL/6 小鼠的巨噬细胞产生更多的 TNF-α 和 IL-6，并且产生的 TNF-α 量取决于 TLR2 和 Dectin-1。来自 C57BL/6 小鼠的 DC 比 DBA/2 DC 产生更多的 IL-10 和更少的 IL-23p19 和 IL-12p70。这些反应被 Dectin-1 的单克隆抗体抑制。 DBA/2 小鼠表达全长 Dectin-1，而 C57BL/6 小鼠则剪接出外显子 3，该外显子编码大部分茎。转导表达全长 Dectin-1 的 RAW 细胞比表达截短 Dectin-1 的细胞对 FKS 的反应更好。我们比较了 34 个 C57BL/6 X DBA/2 重组自交系 (BXD RI) 表达的 Dectin-1 亚型及其对粗球孢子菌的易感性。在 34 个 RI 品系中，有 25 个品系的敏感性或耐药性分别对应于短亚型或全长亚型。这些结果表明，Dectin-1 基因的选择性剪接导致 C57BL/6 小鼠对球孢子菌病的易感性，并影响巨噬细胞和 mDC 对小球的细胞因子反应。
Coccidioides posadasii spherules stimulate macrophages to make cytokines via TLR-2 and Dectin-1. We used formalin-killed spherules and 1,3-beta-glucan purified from spherules to stimulate elicited peritoneal macrophages and myeloid dendritic cells (mDCs) from susceptible (C57BL/6) and resistant (DBA/2) mouse strains. DBA/2 macrophages produced more TNF-alpha and IL-6 than macrophages from C57BL/6 mice, and the amount of TNF-alpha made was dependent on both TLR2 and Dectin-1. DCs from C57BL/6 mice made more IL-10 and less IL-23p19 and IL-12p70 than did DBA/2 DC. These responses were inhibited by a monoclonal antibody to Dectin-1. DBA/2 mice expressed full-length Dectin-1, whereas C57BL/6 mice spliced out exon 3, which encodes most of the stalk. RAW cells transduced to express the full-length Dectin-1 responded better to FKS than cells expressing truncated Dectin-1. We compared the isoform of Dectin-1 expressed by 34 C57BL/6 X DBA/2 recombinant inbred (BXD RI) lines with their susceptibility to Coccidioides immitis. In 25 of 34 RI lines susceptibility or resistance corresponded to short or full-length isoforms, respectively. These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules.