Spatial and temporal features of neutrophils in homeostasis from the perspective of computational biology

Abstract

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 22-07-2022Neutrophils are myeloid cells that originate in the Bone Marrow and enter circulation to patrol for infectious agents. An important part of the “nonspecific” immune system consists on Neutrophils infiltrating challenged tissues, and the established belief was that they stay away from steady-state organs to avoid the risk of exposing them to their cytotoxic content. In the papers presented in this thesis, we show that neutrophils can in fact be found in almost all tissues under homeostasis. We further present proof that they undergo shifts in DNA accessibility, RNA expression and protein content in the infiltrated tissues. Using functional annotation we predict distinct roles depending on the tissue. While in hematopoietic organs the transcriptomic signatures of neutrophils align with canonical functions like immune response and migration, in other tissues such as the skin we find non-canonical functions i.e, epithelial and connective tissue growth or pro-angiogenic roles in the gut and the lung. This predicted pro-angiogenic role was indeed confirmed for the lung. We finally describe that infiltration in tissues follows circadian dynamics, and that once it has occurred, neutrophils experience changes in transcription depending on the time of the day. The analyses of circadian rhythms on mammalian models are often hindered by the inherent difficulty of performing exhaustive sampling (i.e.: every hour for at least 48h). Hence, I implemented CircaN as an R package, which outperforms existing tools in most scenarios. To provide the most complete analysis possible, we provide a full mode analysis option, in which we run CircaN and the two most used algorithms and provide integrated results. We present proof-of-concept results showing that combining various tools yields the best true positive to false positive ratio for most purposesEsta Tesis ha sido financiada por el Ministerio de Ciencia, Innovación y Universidades (MICINN