Female X-Chromosome Mosaicism for NOX2 Deficiency Presents Unique Inflammatory Phenotype and Improves Outcome in Polymicrobial Sepsis
Female X-Chromosome Mosaicism for NOX2 Deficiency Presents Unique Inflammatory Phenotype and Improves Outcome in Polymicrobial Sepsis
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DOI：
10.4049/jimmunol.1100205
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发表时间：
2011-06-01
影响因子：
4.4
通讯作者：
Spolarics, Zoltan
中科院分区：
文献类型：
--
作者：
Chandra, Rachna;Federici, Stephanie;Spolarics, Zoltan
与男性的单一 X 染色体机制相比，女性特有的细胞 X 染色体嵌合体在病理生理挑战中可能具有优势，并且可能导致炎症反应中的性别二态性。我们测试了 X 连锁 gp91phox (NOX2) 缺陷（产生超氧阴离子的 NADPH 氧化酶复合物的催化成分）的细胞嵌合在多种微生物败血症期间是否有利的假设。在盲肠结扎和穿刺引发多种微生物脓毒症后，对缺陷型、野生型 (WT) 和杂合/马赛克小鼠进行了比较。与 WT 同窝小鼠相比，缺陷小鼠以及同时携带缺陷和 WT 吞噬细胞亚群的嵌合动物中脓毒症引起的死亡率有所改善。相比之下，缺陷小鼠的血液细菌计数最高。与较差的存活率一致，WT 小鼠在败血症后也表现出最严重的器官损伤。在嵌合动物中，与同一动物内的 WT 中性粒细胞亚群相比，缺陷的中性粒细胞亚群表现出器官募集增加和 CD11b 膜表达升高。脓毒症引起的血液和器官细胞因子含量以及白细胞组成变化（包括血液和骨髓中的淋巴细胞亚群）的动态显示WT、缺陷和嵌合受试者之间的差异，表明嵌合小鼠不仅仅是缺陷和WT反应的平均值。在氧化爆发后，镶嵌小鼠中野生型和缺陷型中性粒细胞亚群之间发生氧化剂交换。这项研究表明，与 WT 和缺陷小鼠相比，gp91phox 表达的小鼠嵌合体在脓毒症过程中具有多种优势。免疫学杂志，2011，186：6465-6473。
Cellular X-chromosome mosaicism, which is unique to females, may be advantageous during pathophysiological challenges compared with the single X-chromosome machinery of males, and it may contribute to gender dimorphism in the inflammatory response. We tested the hypothesis of whether cellular mosaicism for the X-linked gp91phox (NOX2) deficiency, the catalytic component of the superoxide anion-generating NADPH oxidase complex, is advantageous during polymicrobial sepsis. Deficient, wild-type (WT), and heterozygous/mosaic mice were compared following polymicrobial sepsis initiated by cecal ligation and puncture. Compared with WT littermates, sepsis-induced mortality was improved in deficient mice, as well as in mosaic animals carrying both deficient and WT phagocyte subpopulations. In contrast, blood bacterial counts were greatest in deficient mice. Consistent with poor survival, WT mice also showed the most severe organ damage following sepsis. In mosaic animals, the deficient neutrophil subpopulations displayed increased organ recruitment and elevated CD11b membrane expression compared with WT neutrophil subpopulations within the same animal. The dynamics of sepsis-induced blood and organ cytokine content and WBC composition changes, including lymphocyte subsets in blood and bone marrow, showed differences among WT, deficient, and mosaic subjects, indicating that mosaic mice are not simply the average of the deficient and WT responses. Upon oxidative burst, interchange of oxidants between WT and deficient neutrophil subpopulations occurred in mosaic mice. This study suggests that mice mosaic for gp91phox expression have multiple advantages compared with WT and deficient mice during the septic course. The Journal of Immunology, 2011, 186: 6465-6473.