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Neutrophil subsets in animal models of inflammation and cancer

Friday 15 January 2016

Recently, neutrophils have been described to play a role in the pathogenesis of various human diseases such as cardiovascular disease, cancer, auto-immune diseases and allergy. Linked to these conditions, several neutrophil subsets have been newly described such as low-density granulocytes, granulocytic myeloid-derived suppressor cells (G-MDSC), tumor-associated neutrophils (TAN), and hypersegmented neutrophils. These subsets have altered phenotypes and can have either pro- or anti-inflammatory functionalities, which we are just starting to unravel. The ability to steer neutrophil function, activation or localization would be beneficial for many diseases. The treatment of cancer would likely benefit from targeting only the pro-tumor neutrophil subset as opposed to all neutrophils. In contrast, the treatment of asthma would greatly benefit from targeting only the pro-inflammatory neutrophil subset. But the basic knowledge on the timing, localization or even origin of neutrophil subsets is lacking, because we cannot easily sample human tissues. To aid our understanding, we also want to follow these different neutrophil subsets in animal models. We have been working with acute models such as LPS challenged mice and mice with trauma as well as chronic models such as cancer. We think it is important to understand whether neutrophil subsets observed upon inflammation are the same throughout the range of inflammatory disorders. If they have a different phenotype and/or function for different types of disorders, that would be highly relevant for designing new therapies. In this project we want to investigate whether acute and chronic inflammation can also induce/ recruit neutrophil subsets in mice with similar functionalities as found in human. If so, their presence, recirculation and functionality can be studied in multiple relevant organs. In this research project we will combine data of healthy mice, mice with acute inflammation and mice with chronic inflammation, to help us understand why and when different neutrophil subsets are developed and recruited. In the different mouse models, you will isolate neutrophils and perform ex vivo assays to determine the inflammatory profile and performance of key functions (e.g. migration, killing, T cell interactions). Understanding how and where the different neutrophil subsets arise in inflammatory conditions and what mechanisms underlie their function is essential to determine their role in disease and to establish potential treatment options. Redirection of immune responses has an enormous societal and scientific relevance as inflammation-associated diseases (including cardiovascular disease, cancer, auto-immunity and allergy) are associated with major pathology and morbidity.

FACS, (confocal) microscopy, isolation of lymphocytes and phagocytes from peripheral blood, cell culture, functional assays ex vivo, in vivo animal experiments, two-photon intravital microscopy

6 or 9 months

Dr. Nienke Vrisekoop N.Vrisekoop@umcutrecht.nl
Prof. Dr. Leo Koenderman L.Koenderman@umcutrecht.nl