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The life and death of neutrophils
Croker D'Cruz Necroptosis NET Science Si

We are an inflammation laboratory with a broad interest in the intersection of cell death, neutrophil biology, and innate immunity. Here are some of our recent research programs which seek to understand the pathophysiology of human inflammatory diseases:

  1. We identified roles for GSDME- and MLKL-dependent cell death in neutrophil extracellular trap formation. PAD4 is activated in response to plasma membrane disruption by GSDME and MLKL, and is essential for generation of NETs. Parallel studies of GSDMD-dependent NET formation and non-canonical inflammasome activation provides a genetic framework to explore the relationship between apoptotic and non-apoptotic neutrophil cell death, NET generation, and responses to infection.

  2. We identified a novel Ptpn6 Y208N mutant mouse strain causing cutaneous inflammation of the feet. Mice carrying neutrophil-specific deletions of Ptpn6 develop neutrophilic dermatoses caused by MLKL- and Caspase-8-dependent inflammatory cell death driving IL-1 release.

  3. As part of a U19 grant, we investigate host-pathogen interactions in Coccidioidomycosis. This soil-borne fungal pathogen is prominent in the USA, and central and south America, causing chronic respiratory disease and in severe cases disseminated disease. 

  4. Our laboratory identified a novel phenomena called shuttling in mammalian cells, which involves the transfer of intracellular fungal pathogens from neutrophils to macrophages. We are studying how pathogens captured by neutrophils at distal sites of infection are shuttled to dendritic cells with the greatest capacity for antigen presentation.

  5. clinical study of patients with Kawasaki disease and the COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) identified IL-1b+ neutrophils as a key immune cell targeted by intravenous immunoglobulin using a novel cell death pathway dependent on PI3-kinase and NADPH oxidase. 

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