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Type:	Artigo de Periódico
Title:	Blocking the HGF-MET pathway induces resolution of neutrophilic inflammation by promoting neutrophil apoptosis and efferocytosis
Authors:	Franciel Batistafelix Flávio Almeida Amaral Frederico Marianetti Soriani Mauro Martins Teixeira Vanessa Pinho Julia Dias Juliana Priscila Vago Débora Gonzaga Martins Vinícius Amorim Beltrami Débora de Oliveira Fernandes Anna Clara Paiva Menezes Dos Santos Celso Martins Queiroz-junior Lirlândia Pires de Sousa
Abstract:	Inflammation resolution is an active process that involves cellular events such as apoptosis and efferocytosis, which are key steps in the restoration of tissue homeostasis. Hepatocyte growth factor (HGF) is a growth factor mostly produced by mesenchymal-origin cells and has been described to act via MET receptor tyrosine kinase. The HGF/MET axis is essential for determining the progression and severity of inflammatory and immunemediated disorders. Here, we investigated the effect of blocking the HGF/MET signalling pathway by PF04217903 on the resolution of established models of neutrophilic inflammation. In a self-resolving model of gout induced by MSU crystals, HGF expression on periarticular tissue peaked at 12 h, the same time point that neutrophils reach their maximal accumulation in the joints. The HGF/MET axis was activated in this model, as demonstrated by increased levels of MET phosphorylation in neutrophils (Ly6G+ cells). In addition, the number of neutrophils was reduced in the knee exudate after PF-04217903 treatment, an effect accompanied by increased neutrophil apoptosis and efferocytosis and enhanced expression of Annexin A1, a key molecule for inflammation resolution. Reduced MPO activity, IL-1β and CXCL1 levels were also observed in periarticular tissue. Importantly, PF-04217903 reduced the histopathological score and hypernociceptive response. Similar findings were obtained in LPS-induced neutrophilic pleurisy. In human neutrophils, the combined use of LPS and HGF increased MET phosphorylation and provided a prosurvival signal, whereas blocking MET with PF04217903 induced caspase-dependent neutrophil apoptosis. Taken together, these data demonstrate that blocking HGF/MET signalling may be a potential therapeutic strategy for inducing the resolution of neutrophilic inflammatory responses.
Subject:	Apoptose Inflamação Genética
language:	eng
metadata.dc.publisher.country:	Brasil
Publisher:	Universidade Federal de Minas Gerais
Publisher Initials:	UFMG
metadata.dc.publisher.department:	FAR - DEPARTAMENTO DE ANÁLISES CLÍNICAS E TOXICOLÓGICAS ICB - DEPARTAMENTO DE BIOQUÍMICA E IMUNOLOGIA ICB - DEPARTAMENTO DE FARMACOLOGIA ICB - DEPARTAMENTO DE MORFOLOGIA
Rights:	Acesso Aberto
metadata.dc.identifier.doi:	https://doi.org/10.1016/j.phrs.2022.106640
URI:	http://hdl.handle.net/1843/79379
Issue Date:	Feb-2023
metadata.dc.url.externa:	https://www.sciencedirect.com/science/article/pii/S1043661822005862?via%3Dihub
metadata.dc.relation.ispartof:	Pharmacological Research
Appears in Collections:	Artigo de Periódico

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