Midwood Group | Matrix Immunology
Our group investigates how the extracellular matrix - the component of tissue that lies immediately outside and between cells - contributes to inflammation.
Our immune system is designed to protect us from tissue injury and infection. Inflammation is triggered by pathogen invasion and by endogenous inflammatory molecules that signal tissue damage. Insights into how pathogenic molecules are detected by immune sensors have revealed mechanisms underlying host defence against infection. However, little is known about how endogenous molecules activate immunity. These danger signals are essential for repair following tissue damage, but are also major drivers of chronic sterile inflammation that is the hallmark of autoimmune, fibrotic and metabolic diseases, as well as cancer.
We are investigating how extracellular matrix molecules that are specifically induced upon tissue injury create a microenvironment where infiltrating immune cells and resident stromal cells survive and thrive. Matrix molecules can directly trigger inflammation, exerting control over innate immune responses, for example influencing macrophage plasticity and inflammatory signalling programmes; the cellular environment also dictates site-specific adaptive immunity.
Persistent expression of injury specific matrix molecules drives pathological inflammation, for example during chronic joint inflammation in rheumatoid arthritis and tumor-mediated immunity. The restricted expression of these molecules makes them very tractable targets for drug development, as well as promising candidate disease biomarkers; matrix molecules can reliably predict the onset, and/or the prognosis, of a number of inflammatory disorders and cancers.
Combining structural, molecular, proteomic and genomic approaches we are working towards a better understanding of the biology of endogenously driven immunity, and together with industrial partners, how we might translate this into therapeutic benefit. Dissecting how the extracellular matrix creates a 3D, pro-inflammatory niche that integrates complex mechanical and biochemical immune signals during tissue injury and inflammatory disease presents a number of exciting challenges and current projects include:
1. Defining endogenous inflammatory triggers: Amongst the thousands of molecules that make up ourselves, what defines some as inflammatory triggers, whilst the majority are immunologically silent? How are endogenous stimuli detected by immune sensors? And how are these molecules kept below the radar of immune surveillance until tissue is injured?
2. Distinguishing between inflammatory triggers: All immune responses are not the same; but how does the body distinguish between pathogenic and endogenous inflammatory stimuli, and direct a tailor made immune response to fight infection or repair tissue accordingly?
3. Harnessing the translational potential: Mechanistic differences between pathogenic and endogenous activation of inflammation create the opportunity to selectively inhibit one or the other. Can strategies that block inflammatory signals from the matrix re-educate the immune response, switching off aberrant inflammation, but leaving intact host defence against infection, to safely and effectively treat autoimmune diseases and cancers?