PMID- 27663735
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 113
IP  - 45
DP  - 2016 Nov 8
TI  - Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by 
      methoxyluteolin, a potential therapeutic target for autism.
PG  - E7049-E7058
LID - 10.1073/pnas.1604992113 [doi]
AB  - We had reported elevated serum levels of the peptide neurotensin (NT) in children 
      with autism spectrum disorders (ASD). Here, we show that NT stimulates primary 
      human microglia, the resident immune cells of the brain, and the immortalized 
      cell line of human microglia-SV40. NT (10 nM) increases the gene expression and 
      release (P < 0.001) of the proinflammatory cytokine IL-1beta and chemokine (C-X-C 
      motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from 
      human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. 
      Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. 
      The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated 
      cytokine and chemokine gene expression and release from human microglia. 
      Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 
      0.0001) and causes the receptor to be translocated from the cytoplasm to the cell 
      surface, and to be secreted extracellularly. Our findings also show increased 
      levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), 
      compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes 
      activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown 
      by phosphorylation of its substrates and inhibition of these responses by drugs 
      that prevent mTOR activation. NT-stimulated responses are inhibited by the 
      flavonoid methoxyluteolin (0.1-1 muM). The data provide a link between sortilin 
      and the pathological findings of microglia and inflammation of the brain in ASD. 
      Thus, inhibition of this pathway using methoxyluteolin could provide an effective 
      treatment of ASD.
FAU - Patel, Arti B
AU  - Patel AB
AD  - Molecular Immunopharmacology and Drug Discovery Laboratory, Department of 
      Integrative Physiology and Pathobiology, Tufts University School of Medicine, 
      Boston, MA 02111.
AD  - Graduate Program in Cell, Molecular, and Developmental Biology, Sackler School of 
      Graduate Biomedical Sciences, Tufts University, Boston, MA 02111.
FAU - Tsilioni, Irene
AU  - Tsilioni I
AD  - Molecular Immunopharmacology and Drug Discovery Laboratory, Department of 
      Integrative Physiology and Pathobiology, Tufts University School of Medicine, 
      Boston, MA 02111.
FAU - Leeman, Susan E
AU  - Leeman SE
AUID- ORCID: 0000-0003-2875-1394
AD  - Department of Pharmacology, Boston University School of Medicine, Boston, MA 
      02118; theoharis.theoharides@tufts.edu sleeman@bu.edu.
FAU - Theoharides, Theoharis C
AU  - Theoharides TC
AD  - Molecular Immunopharmacology and Drug Discovery Laboratory, Department of 
      Integrative Physiology and Pathobiology, Tufts University School of Medicine, 
      Boston, MA 02111; theoharis.theoharides@tufts.edu sleeman@bu.edu.
AD  - Graduate Program in Cell, Molecular, and Developmental Biology, Sackler School of 
      Graduate Biomedical Sciences, Tufts University, Boston, MA 02111.
AD  - Department of Internal Medicine, Tufts University School of Medicine and Tufts 
      Medical Center, Boston, MA 02111.
AD  - Department of Psychiatry, Tufts University School of Medicine and Tufts Medical 
      Center, Boston, MA 02111.
LA  - eng
PT  - Journal Article
DEP - 20160923
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
EIN - Proc Natl Acad Sci U S A. 2016 Nov 1;:. PMID: 27803332
PMC - PMC5111711
OTO - NOTNLM
OT  - autism spectrum disorders
OT  - human microglia
OT  - mTOR
OT  - methoxyluteolin
OT  - sortilin
COIS- Conflict of interest statement: T.C.T. has been awarded, under an agreement with 
      Tufts University, the following patents: US 9,050,275 - Methods of Screening for 
      and Treating Autism Spectrum Disorders and Compositions for Same and US 9,176,146 
      - Methods of Treating Autism Spectrum Disorders and Compositions for Same. A 
      Provisional Patent Application was also filed by Tufts University as US 
      62/396,546 - Compositions and Methods of Autism Treatment. T.C.T. is also the 
      Scientific Director of Algonot, LLC (Sarasota, FL) that has developed the 
      flavonoid-containing trademarked dietary supplement NeuroProtek, for which Tufts 
      receives royalties. No portion of the work described in this paper was funded by 
      Algonot.
EDAT- 2016/11/03 06:00
MHDA- 2016/11/03 06:01
PMCR- 2017/05/08
CRDT- 2016/09/25 06:00
PHST- 2016/11/03 06:00 [pubmed]
PHST- 2016/11/03 06:01 [medline]
PHST- 2016/09/25 06:00 [entrez]
PHST- 2017/05/08 00:00 [pmc-release]
AID - 1604992113 [pii]
AID - 201604992 [pii]
AID - 10.1073/pnas.1604992113 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):E7049-E7058. doi: 
      10.1073/pnas.1604992113. Epub 2016 Sep 23.