Olfactomedin 4 is a key regulator of human neutrophil function

Olfactomedin 4 是人类中性粒细胞功能的关键调节剂

• 批准号: 10012677
• 负责人: GRIFFIN RODGERS
• 金额: $ 52.01万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10012677
• 关键词: Amino Acid Sequence; Apoptosis; Attenuated; Bacteria; Biology; CASP3 gene; CASP9 gene; CSF3 gene; Cell Membrane Permeability; Disease; Epithelium; Escherichia coli; Exhibits; Future; Genes; Glycoproteins; Granulocyte Colony-Stimulating Factor; Hematopoietic; Human; Hydrogen Peroxide; Hydroxyl Radical; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferons; Invaded; Laboratories; Link; Malignant Neoplasms; Mediating; Mitochondria; Mitochondrial Proteins; Molecular; Mucous Membrane; Mus; Myelogenous; NADPH Oxidase; Noelin-1; OLFM4 gene; Oxidases; Oxidative Stress; Pathologic; Process; Production; Reactive Oxygen Species; Regulation; Reporting; Role; Superoxides; Translations; Tretinoin; Wild Type Mouse; alpha-latrotoxin receptor; dosage; gastrointestinal infection; inhibitor/antagonist; microorganism; neutrophil; olfactomedin; precursor cell; response

Neutrophils increase production of reactive oxygen species, including superoxide, hydrogen peroxide (H2O2), and hydroxyl radical, to destroy invading microorganisms under pathological conditions. Conversely, oxidative stress conditions, such as the presence of H2O2, induce neutrophil apoptosis, which helps to remove neutrophils after inflammation. However, the detailed molecular mechanisms that are involved in the latter process have not been elucidated. In this study, we investigated the potential role of olfactomedin 4 (Olfm4) in H2O2-induced superoxide production and apoptosis in mouse neutrophils. We have demonstrated that Olfm4 is not required for maximal-dosage PMA- and Escherichia coli bacteria-induced superoxide production, but Olfm4 contributes to suboptimal-dosage PMA- and H2O2-induced superoxide production. Using an NADPH oxidase inhibitor and gp91phox-deficient mouse neutrophils, we found that NAPDH oxidase was required for PMA-stimulated superoxide production and that Olfm4 mediated H2O2-induced superoxide production through NADPH oxidase, in mouse neutrophils. We have shown that neutrophils from Olfm4-deficient mice exhibited reduced H2O2-induced apoptosis compared with neutrophils from wild-type mice. We also demonstrated that neutrophils from Olfm4-deficient mice exhibited reduced H2O2-stimulated mitochondrial damage and membrane permeability, and as well as reduced caspase-3 and caspase-9 activity, compared with neutrophils from wild-type mice. Moreover, the cytoplasmic translocation of the proapoptotic mitochondrial proteins Omi/HtrA2 and Smac/DIABLO in response to H2O2 was reduced in neutrophils from Olfm4-deficient mice compared with neutrophils from wild-type mice. Our study demonstrates that Olfm4 contributes to H2O2-induced NADPH oxidase activation and apoptosis in mouse neutrophils. Olfactomedin 4 might prove to be a potential target for future studies on inflammatory neutrophil biology and for inflammatory disease treatment.

中性粒细胞增加活性氧物质的产生，包括超氧化物、过氧化氢（H2 O2）和羟基自由基，以在病理条件下破坏入侵的微生物。相反，氧化应激条件，如H2 O2的存在，诱导中性粒细胞凋亡，这有助于在炎症后清除中性粒细胞。然而，在后一个过程中所涉及的详细的分子机制尚未阐明。在这项研究中，我们研究了嗅觉调节素4（Olfm 4）在H2 O2诱导的小鼠中性粒细胞超氧化物生成和凋亡中的潜在作用。我们已经证明，Olfm 4是不需要的最大剂量的PMA和大肠杆菌细菌诱导的超氧化物的生产，但Olfm 4有助于次优剂量的PMA和H2 O2诱导的超氧化物的生产。使用NADPH氧化酶抑制剂和gp 91 phox缺陷的小鼠中性粒细胞，我们发现，NAPDH氧化酶所需的PMA刺激的超氧化物的生产和Olfm 4介导的H2 O2诱导的超氧化物的生产，通过NADPH氧化酶，在小鼠中性粒细胞。我们已经表明，与野生型小鼠的中性粒细胞相比，Olfm 4缺陷小鼠的中性粒细胞表现出减少H2 O2诱导的凋亡。我们还表明，从Olfm 4缺陷小鼠的中性粒细胞表现出减少H2 O2刺激的线粒体损伤和膜通透性，以及减少caspase-3和caspase-9的活性，与野生型小鼠的中性粒细胞相比。此外，与野生型小鼠的中性粒细胞相比，Olfm 4缺陷小鼠的中性粒细胞中促凋亡线粒体蛋白Omi/HtrA 2和Smac/DIABLO响应H2 O2的细胞质易位减少。我们的研究表明，Olfm 4有助于H2 O2诱导的NADPH氧化酶激活和小鼠中性粒细胞凋亡。嗅觉调节蛋白4可能被证明是未来炎症中性粒细胞生物学研究和炎症性疾病治疗的潜在靶点。