PTP1B phosphatase dampens iPSC-derived neutrophil motility and antimicrobial function

• Published in: Journal of leukocyte biology Vol. 116; no. 1; pp. 118 - 131
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England 28-06-2024
• Subjects: Actins - metabolism; Aspergillus fumigatus; Cell Movement; Extracellular Traps - immunology; Extracellular Traps - metabolism; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Neutrophils - immunology; Neutrophils - metabolism; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; fungal; phosphatase; stem cell; neutrophil; chemotaxis
• ISSN: 1938-3673; 1938-3673
• 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.