Research Interests

The primary focus of my lab is the study of cell death, especially the natural cell death process known as apoptosis (programmed cell death), as well as unprogrammed cell death (necrosis). We are especially interested in how necrosis can promote activation of the immune system (i.e. promote inflammation), through release of IL-1 family cytokines (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and how apoptosis can also modulate inflammation.

Apoptosis is a mode of cell death that is under molecular control and can be triggered by a multitude of stimuli - both physiological as well as pathological. Cells die by apoptosis during development, tissue homeostasis, fine tuning of the immune system, and due to the normal wear and tear that multicellular organisms experience in everyday life. Apoptosis is also observed as a part of the damage-limitation response seen during infectious disease and is seen during many other pathological conditions, such as cancer and neurodegeneration.

Understanding how and why cells die, at a molecular level, is leading to new insights into many fundamental biological processes as well as new ways of treating conditions where either too few (cancer, autoimmune disease) or too many (neurodegeneration) cells die.

See our publications page for examples of our work in these areas.

Current areas of interest

CELL DEATH AND INFLAMMATION

Necrotic cell death within tissues either instigates inflammation (in sterile injury contexts) or is a key amplifier of inflammation (during infection). In both scenarios, molecules released from dead cells (collectively called DAMPs, damage-associated molecular patterns) trigger inflammation. However, exactly what constitutes a DAMP is the subject of much debate. We are currently exploring the idea that members of the extended IL-1 family constitute the key DAMPs. We are also exploring how DAMPs become inactivated in scenarios where cells die naturally (i.e. via apoptosis) where DAMP release is not warranted. Another line of investigation is exploring how other cell death stimuli trigger conventional pro-inflammatory cytokine/chemokine secretion from dying cells.



ACTIVATION OF IL-1 FAMILY CYTOKINES

Members of the extended IL-1 cytokine family (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) play key roles in the initiation of inflammation and act at the very apex of inflammatory pathways. The latter cytokines all have propeptides of variable length, which require removal (via proteases) to either permit activation of the latter cytokines or to amplify their activity. We have published a series of studies (e.g. Luthi et al., 2009 Immunity; Afonina et al., 2011 Molecular Cell; Henry et al., 2016 Cell Reports) exploring the role of neutrophil proteases as modulators of IL-1 family activation states. This work is ongoing.



PRO-INFLAMMATORY EFFECTS OF DEATH RECEPTOR (FAS, TRAIL, TNF) STIMULATION

Although it is well known that engagement of the Fas/CD95 or TRAIL (DR4/DR5) death receptors can lead to apoptosis, what is much less widely known is these receptors can also promote inflammatory cytokine production ((e.g. see Cullen et al., 2013 Molecular Cell; Henry and Martin 2017 Molecular Cell), and this might explain why these receptors are upregulated on certain tumor populations. We are currently exploring how Fas and TRAIL signaling can be diverted to inflammatory cytokine production and the molecules involved.



USING CYTOKINE 'FINGERPRINTS' TO STRATIFY INFLAMMATORY DISEASES

Many inflammatory diseases are now treatable using cytokine-targeting biologic drugs (e.g. anti-TNF, anti-IL-1, anti-IL-17A, anti-IL-12/IL-23). However, the decision to treat with the latter biologics is typically not informed by specific evidence of activity of the latter cytokines in particular patients. We are exploring ways of determining which driver cytokines are most active in inflammatory diseases through developing 'cytokine fingerprinting' approaches for the detection of distinct patterns of cytokine activity driven by 'apical' cytokines (such as TNF and IL-1 family members).



IMMUNE-RELATED EFFECTS OF CHEMOTHERAPEUTIC DRUGS

Many widely used cancer chemotherapeutic drugs, such as taxol and cisplatin, also trigger additional immune-related effects that could either contribute to their ability to clear tumors, or on the other hand, might help certain tumor cells to survive and re-initiate tumor establishment or metastasis. We are currently investigating these collateral effects to identify the molecular mechanisms involved.



PARKIN-DEPENDENT MITOPHAGY AND CELL DEATH CONTROL

Although Parkin (one of the affected genes in familial Parkinson's disease) has long been implicated in cell death control, the underlying mechanisms remain obscure. We are currently investigating the molecular mechanism of Parkin-mediated mitophagy and Parkin-dependent cell death.



Previous areas of interest

REGULATION OF CELL DEATH AND IMMUNITY BY CASPASES

A family of proteases (called Caspases) are responsible for dismantling the cellular architecture during apoptosis. We have previously explored how caspases become activated during apoptosis, the order of caspase activation events, and how caspase activation results in the apoptotic phenotype. We are currently investigating the role of caspases in immune-related contexts.



REGULATION OF APOPTOSIS AND MITOCHONDRIAL FISSION/FUSION DYNAMICS BY MEMBERS OF THE BCL-2 FAMILY

Apart from their role in the regulation of the onset of cell death, certain members of the Bcl-2 family may have additional roles in other cell processes such as mitochondrial fission/fusion dynamics. This has previously been an area of active investigation in the lab.



THE ROLE OF GRANZYME B AND OTHER GRANZYMES IN CTL AND NK-INITIATED APOPTOSIS

The cytotoxic granules of Natural Killer and cytotoxic T lymphocytes contain a battery of destructive proteases, called granzymes, that these cells use to kill their target cells (virally-infected cells and potentially transformed cells). We have explored how granzymes kill, their molecular targets, and also other roles that these proteases play upon delivery into the target cell, such as processing of IL-1 family cytokines.



THE ROLE OF BH3-ONLY PROTEINS IN SPECIFIC APOPTOTIC PATHWAYS

'BH3-only' proteins act as upstream regulators of apoptosis that connect specific death signals to the cell death machinery. We have also worked on understanding how certain BH3-only proteins are regulated by oncogenes such as Ras and B-Raf.