Open AccessThe c-MET receptor tyrosine kinase contributes to neutrophil-driven pathology in cutaneous leishmaniasis
Author(s) -
Katiuska Passelli,
Borja Prat-Luri,
Margot Merlot,
Michiel Goris,
Massimiliano Mazzone,
Fabienne TacchiniCottier
Publication year - 2022
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1010247
Subject(s) - leishmania mexicana , leishmania major , neutrophil extracellular traps , infiltration (hvac) , leishmania , immunology , lesion , biology , cutaneous leishmaniasis , mertk , downregulation and upregulation , tyrosine kinase , kinase , leishmaniasis , inflammation , receptor tyrosine kinase , signal transduction , pathology , medicine , microbiology and biotechnology , parasite hosting , biochemistry , physics , world wide web , computer science , gene , thermodynamics
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.