Anna Huttenlocher is the Anna Ruth Brummett Professor of Pediatrics and Medical Microbiology and Immunology at the University of Wisconsin Madison. Her research is at the interface of cell biology and immunology and is centered on understanding on neutrophil function during inflammation and host defense. She seeks to dissect how external cues and cell signaling networks regulate neutrophil migration during tissue damage and repair and how this is altered in human disease. Her laboratory has pioneered approaches to visualize and manipulate leukocyte motility using zebrafish and human cells, and using these tools have uncovered new mechanisms that regulate resolution of innate immune inflammation.
Abstract:
Neutrophils are rapidly recruited to sites of infection and are critical for pathogen clearance. Neutropenic patients are at high risk for fungal and bacterial infections and can benefit from granulocyte transfusion therapy. Human induced pluripotent stem cells (iPSCs) could provide a robust source of neutrophil-like cells for infusion as they can be generated in large quantities and do not require a donor. However, dampened intracellular signaling limits their cellular activation and response. We show that we can engineer iPSC-derived neutrophils (iNeutrophils) for enhanced motility and anti-microbial functions. Deletion of the PTP1B phosphatase increased iNeutrophil PI3K and ERK signaling and was associated with increased F-actin polymerization, cell migration and phagocytosis. PTP1B deletion also increased production of inflammatory cytokines, including the neutrophil chemoattractant IL-8. Furthermore, PTP1B-KO iNeutrophils displayed a highly activated morphology and were more responsive to the fungal pathogen Aspergillus fumigatus. KO iNeutrophils efficiently migrated to and clustered on hyphae resulting in inhibition of fungal growth.
