CCR7-dependent neutrophil trafficking as a driver of maladaptive T-cell responses developing during acute and chronic sterile pathologies

Immune cell movement to different parts of the body is paramount to protect our bodies against invading microorganisms. However, this movement is also at the core of development of self-destructive inflammatory diseases such as ischemia reperfusion injury (IRI) (stroke or heart attack), and autoimmune disorders (rheumatoid arthritis, RA), for which no cure have been found yet. Unfortunately, those diseases have with higher proportion amongst East London communities. Therefore, targeting specific molecules controlling immune cell migration is a realistic strategy to treat patients at higher risk, especially those that do not respond well to available treatments. Amongst these key molecules is CCR7. This molecule allows immune cells to enter specific organs named lymphatic ganglions where the harmful and self-destructive immune responses are initiated.  

Our study proposes to investigate how the molecule CCR7 is regulated in a specific immune cell, called neutrophils which is at the centre of the aforementioned diseases. Using state of the art techniques such as confocal microscopy, intravital and live cell imaging, cell migration assays, gene expression sequencing, together with in vivo models recapitulating human diseases of unique genetically modified and/or pharmacologically-treated animals, we will address 1) how TNF triggers the expression and function of CCR7 in neutrophils and can we  pharmacologically manipulate this molecular event both in vitro & in vivo (year 1-2), 2) if CCR7 proficient neutrophils represent a distinct subpopulation of those leukocytes with pathological functions (year 3) and 3) if targeting CCR7 in neutrophils by drugs newly developed in the lab (thanks to the support of Barts Charity) can suppress disease development using pre-clinical lab models recapitulating the human disease of IRI and RA. 

Ultimately, this project will provide a hitherto unexplored therapeutic avenue for controlling immune cell migration and hence their deleterious functions in pathologies with high prevalence in East London communities.