Research

Lipids at the heart of innate immunity

Macrophages sense infection and tissue damage, then mount inflammation that must be both fast and tightly controlled. We study how membrane lipids, cholesterol transport and cellular metabolism set that balance. Our work spans infectious, metabolic and immune-mediated disease.

01NLRP3 · ASC · caspase-1

Inflammasome biology

How is NLRP3 licensed, assembled and switched off? We dissect the molecular signals that drive NLRP3 oligomerisation, ASC speck formation and caspase-1 activation, and the pyroptotic cell death and IL-1β/IL-18 release that follow.

  • NLRP3
  • ASC
  • Caspase-1
  • Pyroptosis
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Current questions include what determines where the NLRP3 inflammasome assembles on organelle membranes, and how this step is controlled. We are particularly interested in how metabolic state – especially lipid metabolism – sets the threshold for activation. To address these questions, we combine genetic models with live-cell imaging, biochemistry and cytokine profiling in primary macrophages.

[Describe figure: e.g. schematic of NLRP3 inflammasome assembly]
[Figure caption]
02Cholesterol · fatty acids · immunity

Lipid metabolism and immune regulation

Lipid pathways, including cholesterol and fatty acid biosynthesis, are central to immune cell function. We study how these lipid and cholesterol pathways control immune signalling, protein localisation, and inflammation. (Anand, 2020; Leishman et al., 2024)

  • Cholesterol biosynthesis
  • Fatty acid biosynthesis
  • Protein localisation
  • Inflammation
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Our 2024 study in Cell Reports showed that fatty acid synthesis promotes NLRP3 inflammasome activation through palmitoylation of NLRP3, a lipid modification that shapes its localisation and activation. We are now asking how other lipid modifications and metabolic states set the threshold for inflammasome activation in macrophages. Understanding these links may reveal ways to dampen harmful inflammation without compromising host defence.

[Describe figure: e.g. cholesterol staining or membrane contact site schematic]
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03Lipidomics · transcriptomics · targets

Integrative omics and therapeutic discovery

We use lipidomics, transcriptomics, and other multiomics approaches to identify molecular pathways that drive inflammation and metabolic dysfunction. This systems-level strategy supports the identification of novel targets and biomarkers for therapeutic intervention relevant to inflammasomes, lipid metabolism, and inflammation.

  • Lipidomics
  • Transcriptomics
  • Multiomics
  • Biomarkers
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By combining lipid profiling with gene-expression data from macrophages, we map how inflammatory stimuli reshape cellular metabolism. Integrating these datasets lets us pinpoint the lipid species and enzymes that act as control points in inflammation. We work closely with mass spectrometry collaborators to translate these findings into candidate targets and biomarkers. 

[Describe figure: e.g. TLR4 signalling schematic or data panel]
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04Lysosomes · cholesterol transport · disease

Cholesterol trafficking and lysosomal storage disorders

Disruptions in cholesterol transport and lysosomal function can profoundly affect immune responses. We study how these defects – frequently seen in lysosomal storage diseases – alter metabolism and drive inflammatory pathology. (de la Roche et al., 2018).

  • Lysosomes
  • Cholesterol transport 
  • Lysosomal storage disease
  • Inflammation
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Our study in the Journal of Cell Biology showed that trafficking of cholesterol to the endoplasmic reticulum is required for NLRP3 inflammasome activation, linking lysosomal cholesterol export to innate immune signalling. Lysosomal storage disorders such as Niemann–Pick disease type C, in which cholesterol accumulates in lysosomes, provide a natural setting to study these connections. We investigate how these defects reshape macrophage metabolism and inflammatory responses, with the aim of identifying new therapeutic approaches.

[Describe figure: e.g. TLR4 signalling schematic or data panel]
[Figure caption]

Approaches

  • Primary macrophages

    Mouse bone-marrow-derived macrophages and genetic models.

  • Lipidomics

    Mass-spectrometry profiling of cellular lipid composition.

  • Imaging

    Live-cell and confocal microscopy of inflammasome assembly and lipid distribution.

  • Biochemistry

    Protein modification, interaction and cytokine-release assays.