Loss of mTORC2 Activity in Neutrophils Impairs Fusion of Granules and Affects Cellular Metabolism Favoring Increased Bacterial Burden in Sepsis

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art_BREDA_Loss_of_mTORC2_Activity_in_Neutrophils_Impairs_Fusion_2021.PDF (2.75 MB)
Citações na Scopus
2
Tipo de produção
article
Data de publicação
2021
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
AMER ASSOC IMMUNOLOGISTS
Autores
BREDA, Cristiane Naffah de Souza
BREDA, Leandro Carvalho Dantas
CARVALHO, Larissa Anastacio da Costa
AMANO, Mariane Tami
TERRA, Fernanda Fernandes
SILVA, Reinaldo Correia
FRAGAS, Matheus Garcia
FORNI, Maria Fernanda
FONSECA, Monique Thais Costa
Citação
JOURNAL OF IMMUNOLOGY, v.207, n.2, p.626-639, 2021
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Sepsis is a complex infectious syndrome in which neutrophil participation is crucial for patient survival. Neutrophils quickly sense and eliminate the pathogen by using different effector mechanisms controlled by metabolic processes. The mammalian target of rapamycin (mTOR) pathway is an important route for metabolic regulation, and its role in neutrophil metabolism has not been fully understood yet, especially the importance of mTOR complex 2 (mTORC2) in the neutrophil effector functions. In this study, we observed that the loss of Rictor (mTORC2 scaffold protein) in primary mouse-derived neutrophils affects their chemotaxis by fMLF and their microbial killing capacity, but not the phagocytic capacity. We found that the microbicidal capacity was impaired in Rictor-deleted neutrophils because of an improper fusion of granules, reducing the hypochlorous acid production. The loss of Rictor also led to metabolic alterations in isolated neutrophils, increasing aerobic glycolysis. Finally, myeloid-Rictor-deleted mice (LysMRic Delta/Delta) also showed an impairment of the microbicidal capacity, increasing the bacterial burden in the Escherichia coli sepsis model. Overall, our results highlight the importance of proper mTORC2 activation for neutrophil effector functions and metabolism during sepsis.
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URI
https://observatorio.fm.usp.br/handle/OPI/44756
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Coleções
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - LIM/13