Functional Rewiring of Neutrophils: From Transcriptional States to Therapeutic Targets
Lead Research Organisation:
UNIVERSITY OF OXFORD
Abstract
Neutrophils are arguably the most important immune cells in the human body. They are essential for the initial defence against infection but also contribute to tissue and vascular damage in many common diseases. For decades, neutrophils were considered homogeneous, transcriptionally inactive, and too risky to target therapeutically. We and others have changed this dogma by uncovering that neutrophils are highly diverse and adaptable, capable of molecular and functional re-wiring.
Neutrophils undergo morphological, transcriptional, and functional changes during development in the bone marrow (BM), where only mature cells normally enter the circulation before migrating into tissues. However, under pathological conditions such as chronic inflammation and cancer, immature neutrophils are mobilised prematurely. Once in the blood or tissues, local signals reshape their differentiation pathways, driving a remarkable diversity of neutrophil states.
At the heart of this process are transcription factors (TFs), which determine neutrophil identity and function in the BM, blood and tissue. We were the first to generate a transcriptional blueprint linking neutrophil maturation to functional responses, and we have identified key TFs that regulate this transition. Our recent analysis of neutrophil developmental stages uncovered new candidate regulators of their functional states and trajectories. We are therefore uniquely positioned to define and validate TF networks that govern neutrophil behaviour across tissues and immune pathologies and to test whether modulating these networks and/or microenvironment cues in disease can restore balance and reduce pathology. Such insights could overturn the prevailing view that neutrophils cannot be targeted therapeutically and open the door to a new class of neutrophil-directed treatments.
This programme is structured around four interrelated work packages designed to answer a series of questions about the fundamental biology of neutrophils, leading to the development of a new class of neutrophil-targeted therapeutics:
Mechanisms of action – What are the key molecular controllers of neutrophil functional states, and how are they organised?
Systemic responses – Can neutrophil phenotypes be reprogrammed by targeting key TFs?
Tissue imprint – How do local tissue environments shape neutrophil states, and can this be exploited to treat disease?
Towards therapeutics – Can key controllers of neutrophil states be translated to human disease?
To address these questions, we will integrate cutting-edge genomic, computational, imaging, molecular, cellular, in vivo mouse, and clinical human models. This multidisciplinary and sustained approach, supported by outstanding research team, will deliver a mechanistic understanding of how neutrophil states are controlled across tissues and disease contexts. It will provide new molecular reference maps, identify therapeutic targets, and ultimately enable the development of stage- and tissue-specific interventions against pathogenic neutrophil states, without the harmful consequences of complete neutrophil depletion.
Neutrophils undergo morphological, transcriptional, and functional changes during development in the bone marrow (BM), where only mature cells normally enter the circulation before migrating into tissues. However, under pathological conditions such as chronic inflammation and cancer, immature neutrophils are mobilised prematurely. Once in the blood or tissues, local signals reshape their differentiation pathways, driving a remarkable diversity of neutrophil states.
At the heart of this process are transcription factors (TFs), which determine neutrophil identity and function in the BM, blood and tissue. We were the first to generate a transcriptional blueprint linking neutrophil maturation to functional responses, and we have identified key TFs that regulate this transition. Our recent analysis of neutrophil developmental stages uncovered new candidate regulators of their functional states and trajectories. We are therefore uniquely positioned to define and validate TF networks that govern neutrophil behaviour across tissues and immune pathologies and to test whether modulating these networks and/or microenvironment cues in disease can restore balance and reduce pathology. Such insights could overturn the prevailing view that neutrophils cannot be targeted therapeutically and open the door to a new class of neutrophil-directed treatments.
This programme is structured around four interrelated work packages designed to answer a series of questions about the fundamental biology of neutrophils, leading to the development of a new class of neutrophil-targeted therapeutics:
Mechanisms of action – What are the key molecular controllers of neutrophil functional states, and how are they organised?
Systemic responses – Can neutrophil phenotypes be reprogrammed by targeting key TFs?
Tissue imprint – How do local tissue environments shape neutrophil states, and can this be exploited to treat disease?
Towards therapeutics – Can key controllers of neutrophil states be translated to human disease?
To address these questions, we will integrate cutting-edge genomic, computational, imaging, molecular, cellular, in vivo mouse, and clinical human models. This multidisciplinary and sustained approach, supported by outstanding research team, will deliver a mechanistic understanding of how neutrophil states are controlled across tissues and disease contexts. It will provide new molecular reference maps, identify therapeutic targets, and ultimately enable the development of stage- and tissue-specific interventions against pathogenic neutrophil states, without the harmful consequences of complete neutrophil depletion.