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Role of infiltrating neutrophils in tissue homeostasis

Periodic Reporting for period 1 - TISSUENEU (Role of infiltrating neutrophils in tissue homeostasis)

Reporting period: 2017-05-01 to 2019-04-30

Neutrophils are immune cells endowed with the capacity to infiltrate multiple tissues during inflammation to fight against pathogens. However, these cells continuously infiltrate most tissues also during steady state. Whereas several studies have addressed neutrophil biology in infiltrated tissues during pathological conditions, it is currently unknown how homeostatic infiltration of neutrophils modulates their behaviour and function and how this could affect the physiology of their targeted tissues. Tissueneu aim to explore neutrophil heterogeneity in tissues during homeostasis and to identify novel functions in these leukocytes that go beyond their role as immune sentinels.

Understanding neutrophils heterogeneity and its impact in tissue physiology is of the utmost importance because different types of neutrophils act as disease-modifying factor in several pathological conditions including cancer, stroke, myocardial infarction, autoimmune disease or tuberculosis. In this research project, we aim to provide a characterization of neutrophil heterogeneity and function during homeostasis. This information will provide a molecular and functional roadtrip of neutrophils biology during health that is currently missing, and will allow exploring how disease shape this heterogeneity and how this affect tissue homeostasis. Our final aim to identify the molecular mechanisms that modulate neutrophil diversity and to develop novel therapeutic approaches to fight disease.
In this research project we have isolated and characterized neutrophil states through different omics approaches in multiple tissues such as the bone marrow, spleen, lung, intestine and skin during homeostasis and we have explored neutrophil functions in silico using bioinformatics approaches and in vivo, studying the effect of neutropenia in normal tissue physiology.

Our results highlight a process of tissue imprinting of neutrophils in the steady state that can be detected even at the protein or RNA level. We characterized a previously undescribed remarkable transcriptional heterogeneity of these cells that accommodates to their target tissue and strongly predicts novel functions of these cells they leave the circulation, including vascular growth in the lungs and intestine. Our data suggest that tissular cues exploit neutrophil plasticity for the unique demands of each organ and indicate that neutrophil heterogeneity is important for normal tissue physiology.
Despite established dogma considering neutrophils as homogeneous cells that have a limited immune role in fighting against pathogens, several studies suggest the neutrophils are in fact a heterogeneous cell population both in the steady state and in disease. We have characterized this heterogeneity and we have now strong evidences of tissue specification and function of neutrophils during steady state. We collected relevant transcriptomic data on several neutrophils populations and identified in silico potential molecular mechanisms that underlie neutrophil heterogeneity, makers for the identification of specific neutrophils subsets and targets for its modulation. All this knowledge will be used to study the detrimental or protective roles of neutrophil heterogeneity in diseases, such as cancer, myocardial infarct or autoimmunity
Neutrophils (green cells) patroling the healthy colon. Neurons (in red) and vessels (in cyan)