PTP1B phosphatase dampens iPSC-derived neutrophil motility and antimicrobial function

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 sour...

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Published in:Journal of leukocyte biology 2024-06, Vol.116 (1), p.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: Article
Language:English
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
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Summary: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.
ISSN:1938-3673
1938-3673
DOI:10.1093/jleuko/qiae039