Inserm Unité Mixte de Recherche, Faculté de Médecine, Dijon, France.
Blood. 2011 Oct 27;118(17):4694-704. doi: 10.1182/blood-2011-03-341255. Epub 2011 Aug 29.
M-CSF-driven differentiation of peripheral blood monocytes is one of the sources of tissue macrophages. In humans and mice, the differentiation process involves the activation of caspases that cleave a limited number of proteins. One of these proteins is nucleophosmin (NPM1), a multifunctional and ubiquitous protein. Here, we show that caspases activated in monocytes exposed to M-CSF cleave NPM1 at D213 to generate a 30-kDa N-terminal fragment. The protein is further cleaved into a 20-kDa fragment, which involves cathepsin B. NPM1 fragments contribute to the limited motility, migration, and phagocytosis capabilities of resting macrophages. Their activation with lipopolysaccharides inhibits proteolytic processes and restores expression of the full-length protein that negatively regulates the transcription of genes encoding inflammatory cytokines (eg, NPM1 is recruited with NF-κB on the MCP1 gene promoter to decrease its transcription). In mice with heterozygous npm gene deletion, cytokine production in response to lipopolysaccharides, including CXCL1 (KC), MCP1, and MIP2, is dramatically enhanced. These results indicate a dual function of NPM1 in M-CSF-differentiated macrophages. Proteolysis of the protein participates in the establishment of a mature macrophage phenotype. In response to inflammatory stimuli, the full-length protein negatively regulates inflammatory cytokine production.
M-CSF 驱动的外周血单核细胞分化是组织巨噬细胞的来源之一。在人类和小鼠中，这个分化过程涉及到激活有限数量的蛋白质的半胱天冬酶。这些蛋白质之一是核仁磷酸蛋白（NPM1），一种多功能且普遍存在的蛋白质。在这里，我们表明，暴露于 M-CSF 的单核细胞中激活的半胱天冬酶在 D213 处切割 NPM1，生成 30 kDa 的 N 端片段。该蛋白进一步被切割成 20 kDa 的片段，涉及组织蛋白酶 B。NPM1 片段有助于静止巨噬细胞的有限迁移、迁移和吞噬能力。用脂多糖激活它们会抑制蛋白水解过程，并恢复全长蛋白的表达，全长蛋白负调控编码炎症细胞因子的基因的转录（例如，NPM1 与 NF-κB 一起募集到 MCP1 基因启动子上，以降低其转录）。在杂合性 npm 基因缺失的小鼠中，对脂多糖的细胞因子产生，包括 CXCL1（KC）、MCP1 和 MIP2，显著增强。这些结果表明 NPM1 在 M-CSF 分化的巨噬细胞中具有双重功能。该蛋白的蛋白水解参与成熟巨噬细胞表型的建立。在炎症刺激下，全长蛋白负调控炎症细胞因子的产生。
