Our research goal is to elucidate mechanisms that control the initiation of inflammatory responses in innate immune cells.
Introduction: Uncontrolled inflammation is the biggest risk factor for most modern-day diseases, from neurodegeneration to cancer and chronic diseases affecting joints and gut. Our research goal is to elucidate mechanisms that control the initiation and duration of inflammatory responses. To accomplish this goal, we study innate sensing and signalling in myeloid cells, such as macrophages, as these cells typically initiate the inflammatory response. Our group investigates how innate cells integrate signals from cytokines (which report on infection or tissue injury) with signals from microbial and tissue-damage sensors to direct the most appropriate effector response.
Major research objectives
1. Initiation of inflammation by surface innate sensors: signal integration between cytokines and microbial or tissue-damage sensors.
Innate immune cells, such as macrophages, are sentinels of tissue homeostasis. We previously described how innate cells integrate signals from inflammatory cytokines with signals from phagocytic receptors and toll like receptors to direct the most appropriate effector response. We also described how myeloid cells communicate with innate effector cells, such as NK cells to instruct their effector responses. As we follow up on these early studies, we currently focus on a poorly characterized channel-like glycoprotein, whose expression is highly induced on macrophages in response to interferons and pathogen sensing, but supressed in response to tissue repair signals. Using genetic approaches, we are characterising a role of this protein in shaping the immune cell crosstalk and the subsequent downstream inflammatory responses.
2. Initiation of inflammation by cytosolic innate sensors: the NLRP3 inflammasome pathway.
a) What is NLRP3 and why it is important: The NLRP3 inflammasome is one critical intracellular sensor of cell and tissue homeostasis that becomes activated in response to pathogen- or tissue-derived danger signals. The activated NLRP3 inflammasome drives the secretion of proinflammatory cytokines IL-1b and IL-18 to initiate the downstream inflammatory responses, while at the same time it induces proinflammatory death of infected and damaged cell. While activation of the NLRP3 inflammasome is beneficial during infections and vaccinations preventing communicable/infectious diseases, excessive and uncontrolled NLRP3 activity also contributes to the development of several inherited diseases such as Cryopyrin-Associated Periodic Syndromes (CAPS), or non-communicable and lifestyle-related diseases, such as Arthritis, Gout, Alzheimer’s, Parkinson’s and aging-associated inflammation and functional decline.
b) How we study NLRP3: In our lab, we study how the NLRP3 pathway activity is ‘turned on and off’ in healthy individuals. Since the previous century has seen a dramatic rise of non-communicable diseases, where overactive NLRP3 pathway contributes to disease pathology, understanding molecular control of NLRP3 activity will be key for future therapeutic interventions allowing control over inflammasome response.
To study this, we and others typically investigate the inflammasome pathway in vitro, in bone marrow- or blood monocyte-derived macrophages. This remains an important step in discovering the basic biology of any signalling pathway. But as a result, we currently know very little about how the inflammasome pathway is regulated in tissue, where the damage, or infection, are first sensed. So, going forward we aim to combine studies of inflammasome biology in vitro with the disease models in vivo (e.g. Arthritis) to investigate how the inflammasome pathway is naturally turned on and off in tissue macrophages, and how it contributes to local inflammation and development of disease.