Catarina Amoedo-Leite: Immune Regulation of Functional Tissue Perfusion: From Ischemic Tissue to Tumor Growth

Abstract

Hypoperfusion of tissue leads to hypoxia and ischemic tissue injury. Restoration of functional blood flow to affected tissue is pivotal to reducing the extent of tissue damage and increasing the quality of life of those suffering. After the onset of ischemia, a strong inflammatory and angiogenic response is initiated, resulting in the rapid recruitment of innate immune cells, macrophages and neutrophils, to the site of injury. In this thesis, several mice models of diseases with an ischemic component here been used to study the role, origin, and recruitment mechanism of macrophages and neutrophils in the development of new and functional vasculature during tissue blood flow restoration.

In Study I, we expanded our understanding of the origins and recruitment mechanisms of Proangiogenic Neutrophils (PANs) and highlighted the importance of the neuro-immune axis in the PAN recruitment to the site of ischemic injury.

In Study II, we highlighted that macrophages in adult ischemic tissue were demonstrated to undergo a cellular program to morphologically, transcriptomically, and functionally resemble mural cells while weakening their macrophage identity. The macrophage-to-mural cell-like phenotypic switch is crucial for restoring tissue function and warrants further exploration as a potential target for immunotherapies to enhance healing.

In Study III, we discovered that PDGFRβ+ macrophages are important for the growth of murine mammary tumors, and their recruitment can be modulated by IGF-1 secretion by other macrophages.

In Study IV, we identify a novel mechanism through which αKG improves cardiac function after heart injury through the polarization of macrophages toward a mural cell-like phenotype.

This thesis outlines novel fuctions of macrophages and neutrophils in regaining tissue function following ischemic injury. Additionally, we have demonstrated the role of these cells in other disease contexts where angiogenesis is essential, such as the tumor microenvironment, and how they are essential for disease progression. This knowledge will help us expand the field of immune therapies, both in the context of ischemic diseases and cancer.