PMID- 34261666
OWN - NLM
STAT- MEDLINE
DCOM- 20211025
LR  - 20211025
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Linking)
VI  - 207
IP  - 2
DP  - 2021 Jul 15
TI  - Loss of mTORC2 Activity in Neutrophils Impairs Fusion of Granules and Affects 
      Cellular Metabolism Favoring Increased Bacterial Burden in Sepsis.
PG  - 626-639
LID - 10.4049/jimmunol.2000573 [doi]
AB  - 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.
CI  - Copyright (c) 2021 by The American Association of Immunologists, Inc.
FAU - Breda, Cristiane Naffah de Souza
AU  - Breda CNS
AUID- ORCID: 0000-0002-9631-1932
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil; criscns@usp.br niels@icb.usp.br.
FAU - Breda, Leandro Carvalho Dantas
AU  - Breda LCD
AUID- ORCID: 0000-0001-9556-1676
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Carvalho, Larissa Anastacio da Costa
AU  - Carvalho LADC
AUID- ORCID: 0000-0001-5720-5910
AD  - Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Sao 
      Paulo, Brazil.
FAU - Amano, Mariane Tami
AU  - Amano MT
AD  - Instituto Sirio-Libanes de Ensino e Pesquisa, Hospital Sirio-Libanes, Sao Paulo, 
      Brazil.
FAU - Terra, Fernanda Fernandes
AU  - Terra FF
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Silva, Reinaldo Correia
AU  - Silva RC
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Fragas, Matheus Garcia
AU  - Fragas MG
AUID- ORCID: 0000-0002-5854-724X
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Forni, Maria Fernanda
AU  - Forni MF
AUID- ORCID: 0000-0002-3335-9023
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
AD  - Horsley Laboratory, Department of Molecular, Cellular and Developmental Biology, 
      Yale University, New Haven, CT.
FAU - Fonseca, Monique Thais Costa
AU  - Fonseca MTC
AUID- ORCID: 0000-0002-7745-5228
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Venturini, Gabriela
AU  - Venturini G
AUID- ORCID: 0000-0003-2913-2296
AD  - Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of 
      Sao Paulo Medical School, Sao Paulo, Brazil.
FAU - Feitosa, Amanda Campelo Melo
AU  - Feitosa ACM
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Ghirotto, Bruno
AU  - Ghirotto B
AUID- ORCID: 0000-0001-6835-3329
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Cruz, Mario Costa
AU  - Cruz MC
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Cunha, Flavia Franco
AU  - Cunha FF
AUID- ORCID: 0000-0001-8209-7421
AD  - Nephrology Division, Laboratory of Clinical and Experimental Immunology, Federal 
      University of Sao Paulo, Sao Paulo, Brazil.
FAU - Ignacio, Aline
AU  - Ignacio A
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Latancia, Marcela
AU  - Latancia M
AUID- ORCID: 0000-0002-3743-7105
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Castoldi, Angela
AU  - Castoldi A
AUID- ORCID: 0000-0002-8434-7989
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Andrade-Oliveira, Vinicius
AU  - Andrade-Oliveira V
AUID- ORCID: 0000-0002-0426-1828
AD  - Federal University of ABC, Natural and Human Sciences Center, Sao Bernardo do 
      Campo, Sao Paulo, Brazil.
FAU - Martins da Silva, Eloisa
AU  - Martins da Silva E
AUID- ORCID: 0000-0002-2230-8810
AD  - Nephrology Division, Laboratory of Clinical and Experimental Immunology, Federal 
      University of Sao Paulo, Sao Paulo, Brazil.
FAU - Hiyane, Meire Ioshie
AU  - Hiyane MI
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil.
FAU - Pereira, Alexandre da Costa
AU  - Pereira ADC
AD  - Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of 
      Sao Paulo Medical School, Sao Paulo, Brazil.
FAU - Festuccia, William
AU  - Festuccia W
AUID- ORCID: 0000-0003-4769-0806
AD  - Department of Physiology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil; and.
FAU - Meotti, Flavia Carla
AU  - Meotti FC
AUID- ORCID: 0000-0002-7217-3352
AD  - Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Sao 
      Paulo, Brazil.
FAU - Camara, Niels Olsen Saraiva
AU  - Camara NOS
AUID- ORCID: 0000-0001-5436-1248
AD  - Department of Immunology, Institute of Biomedical Sciences, University of Sao 
      Paulo, Sao Paulo, Brazil; criscns@usp.br niels@icb.usp.br.
AD  - Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of 
      Sao Paulo Medical School, Sao Paulo, Brazil.
AD  - Department of Medicine, Laboratory of Renal Physiology (LIM 16), University of 
      Sao Paulo, Sao Paulo, Brazil.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210714
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 712K4CDC10 (Hypochlorous Acid)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
SB  - IM
MH  - Animals
MH  - Chemotaxis/physiology
MH  - Escherichia coli/metabolism
MH  - Female
MH  - Glycolysis/physiology
MH  - Humans
MH  - Hypochlorous Acid/metabolism
MH  - Mechanistic Target of Rapamycin Complex 2/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neutrophils/*metabolism
MH  - Phagocytosis/physiology
MH  - Sepsis/*metabolism/*microbiology
MH  - Signal Transduction/physiology
EDAT- 2021/07/16 06:00
MHDA- 2021/10/26 06:00
CRDT- 2021/07/15 05:38
PHST- 2020/05/19 00:00 [received]
PHST- 2021/05/15 00:00 [accepted]
PHST- 2021/07/16 06:00 [pubmed]
PHST- 2021/10/26 06:00 [medline]
PHST- 2021/07/15 05:38 [entrez]
AID - jimmunol.2000573 [pii]
AID - 10.4049/jimmunol.2000573 [doi]
PST - ppublish
SO  - J Immunol. 2021 Jul 15;207(2):626-639. doi: 10.4049/jimmunol.2000573. Epub 2021 
      Jul 14.