Giese Morgan A, Bennin David A, Schoen Taylor J, Peterson Ashley N, Schrope Jonathan H, Brand Josh, Jung Ho Sun, Keller Nancy P, Beebe David J, Dinh Huy Q, Slukvin Igor I, Huttenlocher Anna
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, 1550 Linden Dr. Madison 53706, WI, United States.
Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, 1525 Linden Dr. Madison 53706, WI, United States.
J Leukoc Biol. 2024 Jun 28;116(1):118-131. doi: 10.1093/jleuko/qiae039.
Neutrophils are rapidly recruited to sites of infection and are critical for pathogen clearance. Therapeutic use of primary neutrophils has been limited, as they have a short lifespan and are not amenable to genetic manipulation. Human induced pluripotent stem cells (iPSCs) can provide a robust source of neutrophils for infusion and are genetically tractable. However, current work has indicated that dampened intracellular signaling limits iPSC-derived neutrophil (iNeutrophil) cellular activation and antimicrobial response. Here, we show that protein tyrosine phosphatase 1B (PTP1B) inhibits intracellular signaling and dampens iNeutrophil effector function. Deletion of the PTP1B phosphatase increased PI3K and ERK signaling and was associated with increased F-actin polymerization, cell migration, and phagocytosis. In contrast, other effector functions like NETosis and reactive oxygen species production were reduced. PTP1B-deficient neutrophils were more responsive to Aspergillus fumigatus and displayed rapid recruitment and control of hyphal growth. Accordingly, depletion of PTP1B increased production of inflammatory factors including the neutrophil chemokine interleukin-8. Taken together, these findings suggest that PTP1B limits iNeutrophil motility and antimicrobial function.
中性粒细胞会迅速被招募到感染部位，对病原体清除至关重要。原代中性粒细胞的治疗用途有限，因为它们寿命短且不易进行基因操作。人类诱导多能干细胞（iPSC）可为输注提供大量中性粒细胞来源，并且在基因方面易于操作。然而，目前的研究表明，细胞内信号传导减弱限制了iPSC衍生的中性粒细胞（iNeutrophil）的细胞活化和抗菌反应。在此，我们表明蛋白酪氨酸磷酸酶1B（PTP1B）抑制细胞内信号传导并减弱iNeutrophil效应功能。PTP1B磷酸酶的缺失增加了PI3K和ERK信号传导，并与F-肌动蛋白聚合增加、细胞迁移和吞噬作用相关。相比之下，其他效应功能如中性粒细胞胞外诱捕网形成（NETosis）和活性氧生成则减少。PTP1B缺陷的中性粒细胞对烟曲霉更敏感，并表现出对菌丝生长的快速募集和控制。因此，PTP1B的缺失增加了包括中性粒细胞趋化因子白细胞介素-8在内的炎症因子的产生。综上所述，这些发现表明PTP1B限制了iNeutrophil的运动性和抗菌功能。
