Cardiac Anesthesia Division, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA.
Department of Anaesthesia and Immunology, Harvard Medical School, Boston, MA.
Blood Adv. 2023 Apr 11;7(7):1312-1325. doi: 10.1182/bloodadvances.2022007719.
Sepsis continues to be associated with high morbidity and mortality. Currently, sepsis is managed only conservatively. In sepsis, a substantial number of neutrophils is required, leading to accelerated neutrophil production. Immature neutrophils are released into the circulation to meet a demand, despite their less effective functioning in microbial eradication. Although an intervention to provide more mature neutrophils may serve as a potential sepsis treatment, the mechanism of neutrophil differentiation and maturation remains poorly understood. We discovered that CD11c, traditionally known as a dendritic cell marker, was expressed in neutrophils and regulated neutrophil maturation and effector functions. In the absence of CD11c, neutrophil maturation was impaired in the bone marrow, concomitant with a significant increase in the proliferation and apoptosis of preneutrophils, associated with less effector functions. Under lipopolysaccharide challenge, inducing an emergent neutrophil production in the bone marrow, CD11c deficiency exaggerated the release of immature neutrophils into the circulation, associated with a significant proliferation and apoptosis of preneutrophils. In contrast, constitutively active CD11c knock-in mice showed accelerated neutrophil maturation associated with enhanced effector functions, which further supports the notion that CD11c regulates neutrophil maturation. Furthermore, the constitutively active CD11c knock-in mice offered enhanced bacterial eradication. Taken together, we discovered that CD11c was critical for the regulation of neutrophil maturation, and CD11c activation could serve as a potential target for sepsis treatment.
败血症仍然与高发病率和死亡率相关。目前，败血症仅通过保守治疗进行管理。在败血症中，需要大量的中性粒细胞，导致中性粒细胞加速产生。不成熟的中性粒细胞被释放到循环中以满足需求，尽管它们在微生物清除方面的功能不太有效。虽然提供更多成熟中性粒细胞的干预措施可能作为潜在的败血症治疗方法，但中性粒细胞分化和成熟的机制仍知之甚少。我们发现，CD11c 传统上被认为是树突状细胞的标志物，在中性粒细胞中表达，并调节中性粒细胞的成熟和效应功能。在缺乏 CD11c 的情况下，骨髓中的中性粒细胞成熟受损，同时前中性粒细胞的增殖和凋亡显著增加，与效应功能降低有关。在脂多糖刺激下，诱导骨髓中紧急产生中性粒细胞，CD11c 缺乏会加剧不成熟中性粒细胞释放到循环中，与前中性粒细胞的显著增殖和凋亡有关。相比之下，组成性激活的 CD11c 基因敲入小鼠表现出加速的中性粒细胞成熟，与增强的效应功能相关，这进一步支持了 CD11c 调节中性粒细胞成熟的观点。此外，组成性激活的 CD11c 基因敲入小鼠提供了增强的细菌清除。总之，我们发现 CD11c 对中性粒细胞成熟的调节至关重要，CD11c 的激活可以作为败血症治疗的潜在靶点。
