The p47 GTPases Iigp2 and Irgb10 regulate innate immunity and inflammation to murine Chlamydia psittaci infection
The p47 GTPases Iigp2 and Irgb10 regulate innate immunity and inflammation to murine Chlamydia psittaci infection
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DOI：
10.4049/jimmunol.179.3.1814
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Byrne, Gerald I.
中科院分区：
文献类型：
--
作者：
Miyairi, Isao;Tatireddigari, Venkat R. R. Arva;Byrne, Gerald I.
根据 LD100 测定，C57BL/6J 小鼠对鹦鹉热衣原体感染的抵抗力比 DBA/2J 小鼠高 10(5) 倍。使用 BXD 重组自交系的连锁分析揭示了 11 号染色体上 1.5 Mbp 区域的单个效应基因座，编码三个 p47 GTPases（Irgb10、Igtp 和 Iigp2）簇。感染组织的蛋白质印迹显示，Irgb10 在耐药小鼠中升高，两种可能的 Iigp2 蛋白亚型之一优先在易感小鼠中表达。 BXD39 菌株对 Irgb10 敏感，对 Iigp2 耐药，具有中间表型，表明这些 p47 GTPases 的非冗余作用。 C57BL/6J 和 DBA/2J 在 IFN-γ 依赖性衣原体控制方面表现出差异，这种差异可通过 Iigp2 小干扰 RNA 敲低来逆转。感染腹腔灌洗液的微阵列显示，易感小鼠中中性粒细胞募集趋化因子上调>10倍，耐药小鼠中巨噬细胞分化基因增加>100倍，表明易感性模式涉及不同炎症细胞募集途径的刺激。通过组织学和流式细胞术在易感小鼠中观察到大量中性粒细胞募集，而易感背景的中性粒细胞趋化因子受体（CXCR2）敲除小鼠在致命挑战中幸存下来，证实了中性粒细胞募集是易感性所必需的。同源 Igtp 敲除小鼠也对 Irgb10 和 Iigp2 敏感，在耐药背景下招募中性粒细胞并死于感染。我们得出结论，Irgb10 和 Iigp2 共同作用，赋予对小鼠衣原体感染的不同易感性。数据表明，这些 p47 GTP 酶具有细胞自主效应，可导致截然不同的炎症刺激，导致恢复或死亡。
C57BL/6J mice were 10(5)-fold more resistant to Chlamydia psittaci infection than DBA/2J mice by LD100 determinations. Linkage analysis using BXD recombinant inbred strains revealed a single effector locus at a 1.5-Mbp region on chromosome 11 encoding a cluster of three p47 GTPases (Irgb10, Igtp, and Iigp2). Western blots of infected tissue showed that Irgb10 was elevated in resistant mice and one of the two possible Iigp2 protein isoforms was preferentially expressed in susceptible mice. The BXD39 strain, susceptible at Irgb10 and resistant at Iigp2, had an intermediate phenotype implicating the nonredundant role of these p47 GTPases. C57BL/6J and DBA/2J exhibited a difference in IFN-gamma-dependent chlamydial control, which was reversible by Iigp2 small interfering RNA knockdown. Microarrays of infected peritoneal lavage revealed >10-fold upregulation of neutrophil-recruiting chemokines in susceptible mice and >100-fold increase in macrophage differentiation genes in resistant mice, indicating that the susceptibility pattern involves the stimulation of different inflammatory cell-recruiting pathways. Massive neutrophil recruitment was seen in susceptible mice by histology and flow cytometry, and neutrophil chemokine receptor (CXCR2) knockout mice on a susceptible background survived a lethal challenge, confirming that neutrophil recruitment was required for susceptibility. Congenic Igtp knockout mice also susceptible at Irgb10 and Iigp2 on a resistant background recruited neutrophils and succumbed to infection. We conclude that Irgb10 and Iigp2 act together to confer differential susceptibility against murine chiamydial infection. Data indicate that these p47 GTPases have cell-autonomous effects that result in vastly different inflammatory stimulations, leading to either recovery or death.