Polmann Laura, Grimm Janna Carina, Roth Johannes, Barczyk-Kahlert Katarzyna
Insitute of Immunology, University of Muenster, Roentgenstraße 21, Muenster 48149, Germany.
Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Straße 33, Muenster 48149, Germany.
J Leukoc Biol. 2025 Jun 4;117(6). doi: 10.1093/jleuko/qiaf078.
Neutrophils are the first line of host defense. Neutrophils target invading pathogens by phagocytosis, generation of reactive oxygen species (ROS), neutrophil extracellular trap formation (NETosis), and cytokine production. Interferon regulatory factor 8 (IRF8) plays a central role in the regulation of myeloid cells fate, promoting monocyte and dendritic cell development while inhibiting neutrophil production. The global IRF8 deficiency leads to an accumulation of immature myeloid cells, mostly neutrophils, while IRF8 deficiency restricted to myeloid cells has no effect on myeloid cell differentiation. However, the role of IRF8 in regulating neutrophil function remains to be fully elucidated, especially due to the fact that IRF8 is not expressed in mature neutrophils. This study aims to investigate the impact of IRF8 on effector functions of neutrophils. The absence of IRF8 resulted in a diminished response of neutrophils to inflammatory challenge by lipopolysaccharide (LPS), as evidenced by reduced expression of inflammatory cytokines. This effect was intrinsic to IRF8-/- neutrophils and not driven by extrinsic factors, as assessed comparing bone marrow-derived and estrogen receptor-regulated homeobox B8-derived IRF8-/- neutrophils and was accompanied by reduced p38, extracellular signal-regulated kinase 1/2, and mitogen-activated protein kinase-activated protein kinase 2 activation. It is noteworthy that not all effector functions were affected by IRF8 deficiency. The mechanisms of pathogen elimination, such as phagocytosis and ROS production, were impaired in IRF8-/- neutrophils, whereas processes like NETosis remained entirely intact. In conclusion, our findings suggest that IRF8 shapes the neutrophil response to LPS and modulates neutrophil function, and this process is independent of external factors.
中性粒细胞是宿主防御的第一道防线。中性粒细胞通过吞噬作用、活性氧（ROS）生成、中性粒细胞胞外诱捕网形成（NETosis）和细胞因子产生来靶向入侵病原体。干扰素调节因子8（IRF8）在髓系细胞命运调控中起核心作用，促进单核细胞和树突状细胞发育，同时抑制中性粒细胞生成。全身性IRF8缺陷导致未成熟髓系细胞积聚，主要是中性粒细胞，而仅限于髓系细胞的IRF8缺陷对髓系细胞分化没有影响。然而，IRF8在调节中性粒细胞功能中的作用仍有待充分阐明，尤其是因为IRF8在成熟中性粒细胞中不表达。本研究旨在探讨IRF8对中性粒细胞效应功能的影响。IRF8缺失导致中性粒细胞对脂多糖（LPS）炎症刺激的反应减弱，炎症细胞因子表达降低证明了这一点。这种效应是IRF8-/-中性粒细胞所固有的，而非由外在因素驱动，通过比较骨髓来源和雌激素受体调控的同源盒B8来源的IRF8-/-中性粒细胞评估得出，并且伴随着p38、细胞外信号调节激酶1/2和丝裂原活化蛋白激酶激活的蛋白激酶2激活的降低。值得注意的是，并非所有效应功能都受IRF8缺陷影响。IRF8-/-中性粒细胞中病原体清除机制，如吞噬作用和ROS产生受损，而NETosis等过程则完全保持完整。总之，我们的研究结果表明，IRF8塑造了中性粒细胞对LPS的反应并调节中性粒细胞功能，且这一过程独立于外部因素。
