Inflammation
Resolution

A major focus of my research has been understanding how NETs are cleared under physiological and pathological conditions. During my doctoral studies, I made the first discovery of a physiological NET-induced DNase response, demonstrating that hepatocytes and intestinal epithelial cells rapidly release DNase1 and DNase1L3 following NET formation to maintain extracellular DNA homeostasis. I further showed that hypercholesterolaemia suppresses this protective response through endoplasmic reticulum (ER) stress, leading to impaired NET clearance, sustained inflammation, and accelerated atherosclerosis progression (Arteriosclerosis, Thrombosis, and Vascular Biology; PMID: 34348488).

Building on these findings, I identified macrophages as the principal cellular mediators of NET clearance within tissues. My work demonstrated that macrophage-derived DNases are essential for degrading NETs at sites of chronic inflammation and that activation of the PERK signalling pathway suppresses DNase secretion under hypercholesterolaemic conditions. Furthermore, I showed that persistent NETs directly impair macrophage efferocytosis by inducing proteolytic cleavage of the apoptotic cell receptor MerTK, thereby establishing a mechanistic link between defective NET clearance, impaired inflammation resolution, and progression of advanced atherosclerosis (Circulation Research; PMID: 41031413).

These studies have established a comprehensive framework explaining how NETs are regulated both in the circulation and within tissues and have identified several potential therapeutic strategies aimed at restoring physiological NET clearance in chronic inflammatory diseases.

A central focus of my research has been understanding how macrophages sustain efficient clearance of apoptotic cells (efferocytosis), a fundamental process required for tissue homeostasis and inflammation resolution. Every day, billions of cells undergo apoptosis in the human body, placing an enormous burden on a relatively limited population of professional phagocytes. To maintain tissue homeostasis, individual macrophages must sequentially engulf and degrade multiple apoptotic cells throughout their lifespan. Despite the physiological importance of this process, the cellular and metabolic mechanisms that enable macrophages to sustain prolonged phagocytic activity remain largely unknown.

To address this fundamental question, I investigated the metabolic mechanisms that enable macrophages to sustain prolonged efferocytosis. Using complementary cellular, molecular, metabolic, and advanced imaging approaches, I uncovered a previously unrecognised mechanism that supports sustained macrophage phagocytic function during inflammation resolution. These findings establish a new conceptual framework linking cellular metabolism with macrophage-mediated tissue homeostasis and have broad implications for understanding and therapeutically targeting chronic inflammatory diseases (manuscript in preparation).

In parallel, I demonstrated that efferocytosis stimulates macrophages to release extracellular vesicles (EVs) that actively enhance subsequent apoptotic cell clearance while simultaneously suppressing inflammatory responses. This work identified a previously unrecognised mechanism of intercellular communication during inflammation resolution and established extracellular vesicles as endogenous pro-resolving mediators with significant therapeutic potential for chronic inflammatory diseases. These findings demonstrate that macrophages not only remove dying cells but also actively coordinate tissue repair through EV-mediated signalling, thereby amplifying inflammation resolution (Cell Reports; PMID: 37436891).

To facilitate therapeutic discovery, I established a high-throughput phenotypic screening platform encompassing more than 5,000 FDA-approved and bioactive compounds to identify small molecules capable of enhancing macrophage efferocytosis. This work identified several promising therapeutic candidates and highlights the potential of drug repurposing approaches to restore defective inflammation resolution in cardiovascular and other chronic inflammatory diseases (manuscript in preparation).

Collectively, these studies advance our understanding of the cellular, metabolic, and intercellular mechanisms that govern macrophage-mediated inflammation resolution. By integrating fundamental mechanistic discovery with translational therapeutic approaches, my research provides new conceptual and therapeutic frameworks for enhancing tissue repair and restoring immune homeostasis across a broad spectrum of chronic inflammatory diseases.

During my current postdoctoral research at the Francis Crick Institute, my research has expanded to investigate the fundamental mechanisms by which macrophages coordinate host defence against extracellular fungal pathogens. My work seeks to understand how innate immune cells process complex microbial material following pathogen neutralisation and how these processes shape inflammation resolution, tissue repair, and long-term immune homeostasis.

Building on this work, my current research programme explores how defects in pathogen processing contribute to chronic inflammatory disease. By integrating advanced imaging, cellular immunology, molecular biology, and translational approaches, I aim to define the cellular and molecular mechanisms that maintain immune homeostasis and to identify new therapeutic opportunities for inflammatory and infectious diseases.