How inflammasomes sense changes in tissue environment during inflammation

PROJECT OVERVIEW

 
Macrophages are sentinels of tissue homeostasis; they express sensors that detect presence of infection or tissue injury. Inflammasomes are intracellular sensors in macrophages that become activated upon the loss of cellular homeostasis, for example when cells are stressed, damaged or infected1. Inflammasomes trigger local inflammatory response and make an important part of our antimicrobial defences. However, when inflammasomes are hyper-activated, either due to genetic activating mutations, the consistent persistence of activating signal, or the failure of negative feedback loops, they contribute to chronic inflammation. Examples are inherited inflammatory diseases such as CAPS syndrome, or acquired inflammatory diseases such as Atherosclerosis or Arthritis. How changes in local tissue environment affect level of inflammasome activity, how this activity affects return to homeostasis, and where in the tissue inflammasomes get activated, are still poorly understood questions.

We recently characterised a post-translational break that prevents premature inflammasome activation in response to pathogen or tissue injury signals2. Others2,3 have found that changes in local tissue environment, such as stiffness also control the level of inflammasome activity. Using reporter mice, we have detected active inflammasomes in the swollen synovium upon arthritis induction (unpublished). In this project we propose to (a) test which inflammasomes are able to sense changes in local tissue stiffness; (b) how they affect macrophage response to these changes; and (c) where in the tissue and when inflammasomes become activated during arthritic synovial swelling. This project will combine 3D in vitro tissue models, imaging, biochemistry and in vivo disease models, to understand inflammasome-dependent responses in changing tissue environment. Project will benefit from the inflammasome expertise of the PI (Bezbradica), mechano-sensing expertise of co-I (Wann) and macrophage biology in arthritis5 expertise of co-I (Udalova). 

KEYWORDS

Inflammasomes, macrophages, arthritis.

TRAINING OPPORTUNITIES

Biochemistry, imaging, in vitro functional assays, in vivo disease (arthritis) studies.

KEY PUBLICATIONS

1. Pandey A et al...,Si Ming Man. Cell biology of inflammasome activation (2021) Trends in cell biology DOI:https://doi.org/10.1016/j.tcb.2021.06.010.
2. Fischer, F.A et al...Di Daniel, E., Bezbradica, J.S. TBK1/IKKe act as an OFF switch to limit NLRP3 inflammasome pathway activation (2021) PNAS, doi: 10.1073/pnas.2009309118.
3. Escolano J et al...Bryant C, Guck J. Compliant Substrates Enhance Macrophage Cytokine Release and NLRP3 Inflammasome Formation During Their Pro-Inflammatory Response. (2021) Front Cell Dev Biol. 2021; 9: 639815.
4. Barone D et al...Bryant C Prevention of the foreign body response to implantable medical devices by inflammasome inhibition (2022) PNAS doi.org/10.1073/pnas.2115857119
5. Udalova et al Macrophage heterogeneity in the context of rheumatoid arthritis (2016) Nature Reviews Immunology, 12, pages 472–485

KEY THEMES

Inflammasomes, immunology, chronic inflammatory disease