Abstract
Neutrophils are the first line of defence against invading pathogens. Although neutrophils are well-known professional killers, some pathogens including Leishmania (L.) parasites survive in neutrophils, using these cells to establish infection. Manipulation of neutrophil recruitment to the infection site is therefore of interest in this cutaneous disease. The c-MET tyrosine kinase receptor was shown to promote neutrophil migration to inflamed sites. Here, we investigated the importance of c-MET expression on neutrophils in their recruitment to the infection site and the role of c-Met expression in the pathology of leishmaniasis. Following infection with L. mexicana, mice with conditional deletion of c-MET in neutrophils controlled significantly better their lesion development and parasite burden compared to similarly infected wild type mice. Our data reveal a specific role for c-MET activation in Leishmania-induced neutrophil infiltration, a process correlating with their negative role in the pathology of the diseases. We further show that c-MET phosphorylation is observed in established cutaneous lesions. Exposure to L. mexicana upregulated c-Met expression predominantly in infected neutrophils and c-Met expression influenced ROS release by neutrophils. In addition, pharmacological inhibition of c-MET, administrated once the lesion is established, induced a significant decrease in lesion size associated with diminished infiltration of neutrophils. Both genetic ablation of c-MET in neutrophils and systemic inhibition of c-MET locally resulted in higher levels of CD4+T cells producing IFNγ, suggesting a crosstalk between neutrophils and these cells. Collectively, our data show that c-MET activation in neutrophils contributes to their recruitment following infection, and that L. mexicana induction of c-MET on neutrophils impacts the local pathology associated with this disease. Our results suggest a potential use for this inhibitor in the control of the cutaneous lesion during this parasitic infection.
Highlights
Introduction cMET is a tyrosine kinase encoded by the c-MET proto-oncogene, it is the only known receptor for the hepatocyte growth factor (HGF)
We investigated the role of the c-MET receptor tyrosine kinase in the outcome of cutaneous leishmaniasis. c-MET has been shown to be involved in neutrophil recruitment to inflamed sites
The results presented here reveal that c-MET is contributing to the pathology induced by L. mexicana and suggest that the use of c-MET inhibitors could ameliorate the cutaneous lesion pathology
Summary
Introduction cMET is a tyrosine kinase encoded by the c-MET proto-oncogene, it is the only known receptor for the hepatocyte growth factor (HGF). HGF/c-MET signalling regulates numerous biological pathways such as proliferation, survival, migration and tissue regeneration [1]. Aberrant activation of c-MET signalling has been shown to participate in tumour progression [2,3,4,5], prompting the development of c-MET inhibitors. C-MET inhibitors showed only limited success in clinical trials [6]. This restricted efficacy of systemic c-MET inhibition in cancer is in part related to the inhibition of c-MET in neutrophils. CMET was shown to be crucial for the recruitment of anti-tumoral neutrophils, that kill cancer cells following nitric oxide production [7]
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