RESEARCH

The life and death of neutrophils
Croker_MISC_COVID_UCSD_Kawasaki.jpg
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 the MLKL-dependent cell death pathway in neutrophil extracellular trap formation. PAD4 is activated downstream of MLKL, and was essential for generation of NETs but surprisingly was not required for chromatin decondensation. This work has revealed a novel signaling pathway controlled by MLKL. Parallel studies of GSDMD-dependent NET formation and non-canonical inflammasome activation provides a genetic framework to explore the relationship between 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. Our research team supports ongoing efforts in the UCSD BSL-3 to understand the cytopathic effects of new mutant strains of SARS-CoV-2. We are working to characterize apoptosis pathways triggered by SARS-CoV-2 infection and the neutralizing activity of different classes of monoclonal antibodies

  4. Our laboratory identified a novel phenomena called shuttling in mammalian cells, which involves the transfer of intracellular fungal pathogens from neutrophils to macrophages. Shuttling of fungal and bacterial particles from neutrophils to macrophages is likely to influence the viability and dissemination of pathogens within the host. 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.