PMID- 23720022
OWN - NLM
STAT- MEDLINE
DCOM- 20131028
LR  - 20220408
IS  - 1522-1563 (Electronic)
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 305
IP  - 3
DP  - 2013 Aug 1
TI  - Pivotal role for the mTOR pathway in the formation of neutrophil extracellular 
      traps via regulation of autophagy.
PG  - C348-54
LID - 10.1152/ajpcell.00108.2013 [doi]
AB  - Autophagy is an essential cellular mechanism for cell homeostasis and survival by 
      which damaged cellular proteins are sequestered in autophagosomal vesicles and 
      cleared through lysosomal machinery. The autophagy pathway also plays an 
      important role in immunity and inflammation via pathogen clearance mechanisms 
      mediated by immune cells, including macrophages and neutrophils. In particular, 
      recent studies have revealed that autophagic activity is required for the release 
      of neutrophil extracellular traps (NETs), representing a distinct form of active 
      neutrophil death, namely NETosis. Although NET formation is beneficial during 
      host defense against invading pathogens, the mechanisms that promote excessive 
      NETosis under pathological conditions remain ill defined. In the present study, 
      we aimed to characterize the role of the mammalian target of rapamycin (mTOR) in 
      NETosis. As mTOR kinase is known as a key regulator of autophagy in many 
      mammalian cells including neutrophils, we hypothesized that mTOR may play a 
      regulatory role in NET release by regulating autophagic activity. Our data show 
      that the pharmacological inhibition of the mTOR pathway accelerated the rate of 
      NET release following neutrophil stimulation with the bacteria-derived peptide 
      formyl-Met-Leu-Phe (fMLP), while autophagosome formation was enhanced by mTOR 
      inhibitors. This increased mTOR-dependent NET release was sensitive to inhibition 
      of respiratory burst or blockade of cytoskeletal dynamics. Overall, this study 
      demonstrates a pivotal role for the mTOR pathway in coordinating intracellular 
      signaling events downstream of neutrophil activation leading to NETosis.
FAU - Itakura, Asako
AU  - Itakura A
AD  - Department of Cell and Developmental Biology, Oregon Health & Science University, 
      Portland, Oregon, USA. itakura@ohsu.edu
FAU - McCarty, Owen J T
AU  - McCarty OJ
LA  - eng
GR  - R01-HL-101972/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130529
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - 65929-03-5 (formylmethionyl-leucyl-phenylalanine methyl ester)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Autophagy/*physiology
MH  - DNA/metabolism
MH  - Humans
MH  - N-Formylmethionine Leucyl-Phenylalanine/analogs & derivatives/pharmacology
MH  - *Neutrophil Activation
MH  - Neutrophils/cytology/immunology/*metabolism
MH  - Phagocytosis
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
PMC - PMC3742850
OTO - NOTNLM
OT  - autophagy
OT  - histones
OT  - mTOR
OT  - neutrophil
OT  - neutrophil extracellular traps
EDAT- 2013/05/31 06:00
MHDA- 2013/10/29 06:00
PMCR- 2014/08/01
CRDT- 2013/05/31 06:00
PHST- 2013/05/31 06:00 [entrez]
PHST- 2013/05/31 06:00 [pubmed]
PHST- 2013/10/29 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - ajpcell.00108.2013 [pii]
AID - C-00108-2013 [pii]
AID - 10.1152/ajpcell.00108.2013 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2013 Aug 1;305(3):C348-54. doi: 
      10.1152/ajpcell.00108.2013. Epub 2013 May 29.