Neutrophilic HGF-MET signaling exacerbates intestinal inflammation.
BACKGROUND AND AIMS
Ulcerative colitis (UC) is associated with excessive neutrophil infiltration and collateral tissue damage, but the link is not yet completely understood. Since c-MET receptor tyrosine kinase (MET) is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF), we aimed to identify the function of HGF-MET signalling in neutrophils in UC patients and in mice during intestinal inflammation.


METHODS
Serum and colonic biopsies from healthy controls and UC patients with active (Mayo endoscopic sub score 2-3) and inactive (Mayo endoscopic sub score 0-1) disease were collected to assess the level of serum and colonic HGF. Disease progression and immune cell infiltration was assessed during DSS colitis in wild type and MRP8-Cre MET-LoxP mice.


RESULTS
Increased mucosal HGF expression was detected in patients with active UC, and in mice during the inflammatory phase of DSS colitis. Similarly, serum HGF was significantly increased in active UC patients and positively correlated with C-reactive protein and blood neutrophil counts. Flow cytometric analysis also demonstrated an upregulation of colonic MET+ neutrophils during DSS colitis. Genetic ablation of MET in neutrophils reduced the severity of DSS-induced colitis. Concomitantly, there was a decreased number of TH17 cells, which could be due to a decreased production of IL-1β by MET deficient neutrophils.


CONCLUSION
These data highlight the central role of neutrophilic HGF-MET signalling in exacerbating damage during intestinal inflammation. Hence, selective blockade of this pathway in neutrophils could be considered as a novel therapeutic approach in UC.
['Stakenborg|Michelle|M|', 'Verstockt|Bram|B|', 'Meroni|Elisa|E|', 'Goverse|Gera|G|', 'De Simone|Veronica|V|', 'Verstockt|Sare|S|', 'Di Matteo|Mario|M|', 'Czarnewski|Paulo|P|', 'Villablanca|Eduardo J|EJ|', 'Ferrante|Marc|M|', 'Boeckxstaens|Guy E|GE|', 'Mazzone|Massimiliano|M|', 'Vermeire|Séverine|S|', 'Matteoli|Gianluca|G|']
Neutrophils Ulcerative Colitis (UC) receptor tyrosine kinase (MET)-hepatocyte growth factor (HGF) signalling