Inflammation, Chimiokines et Immunopathologie, INSERM UMR996, Univ. Paris-Sud, Université Paris-Saclay,Châtenay-Malabry, France.
Laboratoire d'immunologie, « Autoimmunité et Hypersensibilités », Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
PLoS One. 2019 Aug 16;14(8):e0216465. doi: 10.1371/journal.pone.0216465. eCollection 2019.
Polymorphonuclear neutrophils (PMNs) are the first line of defense against pathogens and their activation needs to be tightly regulated in order to limit deleterious effects. Nrf2 (Nuclear factor (erythroïd-derived 2)-like 2) transcription factor regulates oxidative stress and/or represses inflammation in various cells such as dendritic cells or macrophages. However, its involvement in PMN biology is still unclear. Using Nrf2 KO mice, we thus aimed to investigate the protective role of Nrf2 in various PMN functions such as oxidative burst, netosis, migration, cytokine production and phagocytosis, mainly in response to zymosan. We found that zymosan induced Nrf2 accumulation in PMNs leading to the upregulation of some target genes including Hmox-1, Nqo1 and Cat. Nrf2 was able to decrease zymosan-induced PMN oxidative burst; sulforaphane-induced Nrf2 hyperexpression confirmed its implication. Tnfα, Ccl3 and Cxcl2 gene transcription was decreased in zymosan-stimulated Nrf2 KO PMNs, suggesting a role for Nrf2 in the regulation of proinflammatory cytokine production. However, Nrf2 was not involved in phagocytosis. Finally, spontaneous migration of Nrf2 KO PMNs was lower than that of WT PMNs. Moreover, in response to low concentrations of CXCL2 or CXCL12, Nrf2 KO PMN migration was decreased despite similar CXCR2 and CXCR4 expression and ATP levels in PMNs from both genotypes. Nrf2 thus seems to be required for an optimal migration. Altogether these results suggest that Nrf2 has a protective role in several PMN functions. In particular, it downregulates their activation in response to zymosan and is required for an adequate migration.
多形核粒细胞（PMN）是抵御病原体的第一道防线，其激活需要严格调控，以限制有害作用。Nrf2（核因子（红细胞衍生 2）样 2）转录因子调节氧化应激和/或抑制树突状细胞或巨噬细胞等各种细胞中的炎症。然而，其在PMN 生物学中的作用尚不清楚。因此，我们使用 Nrf2 KO 小鼠，旨在研究 Nrf2 在各种 PMN 功能（如氧化爆发、网质细胞形成、迁移、细胞因子产生和吞噬作用）中的保护作用，主要针对酵母聚糖。我们发现酵母聚糖诱导 PMN 中 Nrf2 的积累，导致一些靶基因（包括 Hmox-1、Nqo1 和 Cat）的上调。Nrf2 能够减少酵母聚糖诱导的 PMN 氧化爆发；诱导 Nrf2 过度表达的萝卜硫素证实了其作用。在酵母聚糖刺激的 Nrf2 KO PMN 中，TNFα、CCL3 和 CXCL2 基因转录减少，表明 Nrf2 在调节促炎细胞因子产生中起作用。然而，Nrf2 不参与吞噬作用。最后，Nrf2 KO PMN 的自发迁移低于 WT PMN。此外，尽管两种基因型的 PMN 中 CXCR2 和 CXCR4 表达和 ATP 水平相似，但低浓度的 CXCL2 或 CXCL12 刺激时，Nrf2 KO PMN 的迁移减少。因此，Nrf2 似乎是适当迁移所必需的。综上所述，这些结果表明 Nrf2 在几种 PMN 功能中具有保护作用。特别是，它下调 PMN 对酵母聚糖的激活作用，并需要适当的迁移。
