Molecular Mechanisms of Inflammation
Inflammation is the response of the body to infection or injury. It is initiated when immune cells sense the presence of danger to remove the threat and release pro-inflammatory molecules to alert other cells of the unusual situation. Inflammation is a beneficial process to remove an infection (bacteria or virus). However inflammation can be detrimental when it becomes chronic or is induced by signals that come from within our bodies (i.e. molecules that in healthy conditions should not be present outside of cells, such as cholesterol crystals found in atherosclerosis). The incidence of pathologies with a strong inflammatory component such as atherosclerosis, arthritis, Alzheimer or cancer has seriously increased in recent years and novel and innovative treatments are urgently required.
Our research investigates how inflammation is controlled by immune cells such as macrophages to better understand how these can switch inflammation on and off. This knowledge will contribute to the design new specific drugs to block the inflammatory process, leading to the development of effective and novel anti-inflammatory therapies.
What we do
We study the regulation of the inflammasome. This is a molecular complex assembled by immune cells in response to danger signals of both pathogenic (bacteria, virus) and non-pathogenic (i.e. extracellular ATP, cholesterol crystals) origin. This process is crucial for the release of potent pro-inflammatory cytokines such as interleukin-1β or interleukin-18 and to mount an appropriate inflammatory response. Its deregulation can have serious consequences for health and mutations in some of the components that form this complex cause inflammatory periodic syndromes known as CAPs (Cryopyrin Associated Periodic syndromes).
Our research focus in two main areas:
- Molecular mechanisms that govern inflammasome activation. We have shown that deubiquitinases (DUBs), enzymes that remove ubiquitin from proteins, are required for the assembly and activation of the inflammasome. We are currently investigating how post-translational modifications such as ubiquitination, regulate the assembly of this complex and the role that danger signals play in this process.
- Novel functions of the inflamamsome. In addition to the release of inflammatory cytokines, inflammasome activation triggers a process of cell death known as pyroptosis. It has been recently described that pyroptosis leads to the release of protein aggregates that alert other cells to expand inflammation. We are currently investigating novel ways by which the inflammasome contribute to inflammation both intra and extracellularly.
Lopez-Castejon G, Luheshi NM, Compan V, High S, Whitehead RC, Flitsch S, Kirov A, Prudovsky I, Swanton E, Brough D (2013). Deubiquitinases Regulate the Activity of Caspase-1 and Interleukin-1β Secretion via Assembly of the Inflammasome. The Journal of Biological Chemistry. 288(4):2721-33.
Compan V, Baroja-Mazo A, López-Castejón G, Gomez AI, Martínez CM, Angosto D, Montero MT, Herranz AS, Bazán E, Reimers D, Mulero V, Pelegrín P (2012). Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 37(3):487-500.
López-Castejón G, Corbett D, Roberts IS, Brough D (2012). Inhibition of Calpain blocks the phagosomal escape of Listeria monocytogenes. PLOS One. April; 7(4):e35936.
Luheshi NM, Giles JA, López-Castejón G, Brough D (2011). Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages. European Journal of Immunology. Mar; 42(3); 716-25.
Lopez-Castejón G, Baroja-Mazo A, Pelegrín P (2011). Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules. Cellular and Molecular Life Sciences. 68(18):3095-107.
López-Castejón G, Theaker J, Pelegrin P, Clifton A, Braddock M and Surprenant A (2010). P2X7 receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases. The Journal of Immunology, Aug 15; 185(4):2611-9.