Severe influenza A virus infection typically triggers excessive and detrimental lung inflammation with massive cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor playing roles in bone formation and spermatogenesis, in regulating antiviral immune response and immunopathology. Nmp4-deficient mice are protected from H1N1 influenza infection, losing only 5% body weight compared to a 20% weight loss in wild type mice. While having no effects on viral clearance or CD8/CD4 T cell or humoral responses, deficiency of Nmp4 in either lung structural cells or hematopoietic cells significantly reduces the recruitment of monocytes and neutrophils to the lungs. Consistent with fewer innate cells in the airways, influenza-infected Nmp4-deficient mice have significantly decreased expression of chemokine genes Ccl2, Ccl7 and Cxcl1 as well as pro-inflammatory cytokine genes Il1b and Il6. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes and regulates their expression in mouse lung epithelial cells and macrophages. Our data suggest that NMP4 functions to promote monocyte- and neutrophil-attracting chemokine expression upon influenza A infection, resulting in exaggerated innate inflammation and lung tissue damage.

严重的甲型流感病毒感染通常会引发过度和有害的肺部炎症，并伴有大量细胞浸润以及细胞因子和趋化因子的过度产生。我们确定了核基质蛋白 4 (NMP4) 的新功能，NMP4 是一种含锌指的转录因子，在骨形成和精子发生中发挥作用，可调节抗病毒免疫反应和免疫病理学。Nmp4 缺陷小鼠免受 H1N1 流感感染，仅减轻 5% 的体重，而野生型小鼠体重减轻 20%。虽然对病毒清除或 CD8/CD4 T 细胞或体液反应没有影响，但 Nmp4缺乏在肺结构细胞或造血细胞中，显着减少单核细胞和中性粒细胞向肺部的募集。与气道中较少的先天细胞一致，流感感染的Nmp4 缺陷小鼠的趋化因子基因Ccl2、Ccl7和Cxcl1以及促炎细胞因子基因Il1b和Il6的表达显着降低. 此外，NMP4 与趋化因子基因的启动子和/或保守的非编码序列结合，并调节它们在小鼠肺上皮细胞和巨噬细胞中的表达。我们的数据表明，NMP4 可在甲型流感病毒感染后促进单核细胞和嗜中性粒细胞趋化因子的表达，从而导致先天性炎症和肺组织损伤加剧。