A single macrophage can build a protein complex called the NLRP3 inflammasome that drives inflammation, but scientists still do not understand how the cell controls this process in space and time. This project addresses a fundamental gap: how does a healthy cell coordinate the assembly of an inflammasome, and what goes wrong in disease? The researchers propose that the cell rearranges its internal compartments—moving organelles and membranes—to provide a platform for inflammasome formation. They will track how different activating stimuli alter organelle position and shape, and map the network of proteins that recruit NLRP3 to these membranes. This is fundamental cellular biology. The NLRP3 inflammasome is known to worsen major cardiovascular, metabolic, and neurological diseases, so understanding its spatial and temporal control could eventually reveal new targets for anti-inflammatory drugs. But the immediate goal is to explain a basic cellular process that has remained opaque for decades. Similar fundamental work on protein complexes has previously unlocked entirely unexpected therapeutic avenues—for example, how understanding the ribosome led to antibiotics that target bacterial protein synthesis without harming human cells.
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Inflammasomes are multi-molecular protein complexes that play key roles in amplifying inflammatory responses in different disease settings. For many years we have known that a cell, typically a macrophage, is able to generate a single inflammasome complex that will catalyse the unconventional secretion of interleukin-1 (IL-1) family cytokines and thus drive inflammation. However, we still have very little understanding of the cellular mechanisms that coordinate and control inflammasome formation, both in the healthy state and in disease. In this application we will explore new concepts to better understand inflammasome activation. Principally we propose that a cell coordinates inflammasome formation through the spatial remodelling of its intracellular cytoplasmic compartment leading to inflammasome formation on endolysosomal/organelle membranes. Here we propose studying the effects of diverse NLRP3-inflammasome activating stimuli on organelle position, morphology, and dynamics, and to investigate the interactome of endogenous NLRP3 that coordinates its membrane recruitment and activation in space and time. Thus, here we will examine the temporal and spatial molecular interactions that govern control of inflammasome-dependent inflammation. Importantly, we aim to translate the basic mechanistic cellular work into an in vivo context to understand mechanisms of inflammasome activation in an organism. The NLRP3 inflammasome is known to contribute to the worsening of major cardiovascular, metabolic, and neurological diseases and so our findings will be directly relevant to the therapeutic targeting of NLRP3-dependent inflammation.
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