The life and death of neutrophils
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:
Research led by Dr. Akshay D’Cruz identified roles for MLKL-dependent lytic cell death pathways in neutrophil extracellular trap formation. PAD4 was shown to be activated downstream of MLKL, and was essential for generation of NETs but surprisingly was not required for chromatin condensation. This work has revealed entire new signaling pathways controlled by MLKL activation. Parallel studies of GSDMD-dependent canonical NET formation and non-canonical inflammasome activation provides a framework for neutrophil biologists to explore the relationship between non-apoptotic neutrophil cell death, NET generation, and responses to infection.
We identified a novel Ptpn6 Y208N mutant mouse strain causing cutaneous inflammation of the feet. A research team led by Dr. Mary Speir has now demonstrated that mice carrying neutrophil-specific deletions of Ptpn6 develop neutrophilic dermatoses caused by MLKL- and Caspase-8-dependent inflammatory cell death driving IL-1 release.
Our research 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 monoclonal antibodies. Our research uses new image analysis tools to track the spread of individual SARS-CoV-2 virions to neighboring cells.
The laboratory also identified a novel phenomena called shuttling in mammalian cells, which involves the transfer of intracellular 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, but also likely serves to influence antigen presentation. We hypothesize that shuttling has evolved to facilitate antigen presentation by enabling pathogens captured at distal sites of infection to be transported by neutrophils to cells such as dendritic cells with the greatest capacity for antigen presentation.