Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Proceedings of the National Academy of Sciences of the United States of America

Volumn 113, Issue 45, 2016, Pages E7049-E7058

  Patel, Arti B ^a,b   Tsilioni, Irene ^a   Leeman, Susan E ^c   Theoharides, Theoharis C ^a,b,d  

^a TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b TUFTS UNIVERSITY   (United States)

^c BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d TUFTS MEDICAL CENTER   (United States)

Author keywords

Autism spectrum disorders; Human microglia; Methoxyluteolin; MTOR; Sortilin

Indexed keywords

ARTICLE; ERROR; PRIORITY JOURNAL;

EID: 84994482748     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1604992113     Document Type: Article

References (94)

1. Lai MC, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383(9920):896-910.
2. Volkmar FR, McPartland JC (2014) From Kanner to DSM-5: Autism as an evolving diagnostic concept. Annu Rev Clin Psychol 10:193-212.
3. Zablotsky B, Black LI, Maenner MJ, Schieve LA, Blumberg SJ (2015) Estimated prevalence of autism and other developmental disabilities following questionnaire changes in 2014 national health interview survey. Natl Health Stat Report 87:1-20.
4. Willsey AJ, State MW (2015) Autism spectrum disorders: From genes to neurobiology. Curr Opin Neurobiol 30:92-99.
5. Kemper TL, Bauman ML (2002) Neuropathology of infantile autism. Mol Psychiatry 7(Suppl 2):S12-S13.
6. Paolicelli RC, et al. (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456-1458.
7. Shemer A, Erny D, Jung S, Prinz M (2015) Microglia plasticity during health and disease: An immunological perspective. Trends Immunol 36(10):614-624.
8. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57(1):67-81.
9. Morgan JT, et al. (2010) Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol Psychiatry 68(4):368-376.
10. Rodriguez JI, Kern JK (2011) Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol 7(2-4):205-213.
11. Morgan JT, Barger N, Amaral DG, Schumann CM (2014) Stereological study of amygdala glial populations in adolescents and adults with autism spectrum disorder. PLoS One 9(10):e110356.
12. Suzuki K, et al. (2013) Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70(1):49-58.
13. Edmonson C, Ziats MN, Rennert OM (2014) Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism 5(1):3.
14. Pannell M, Szulzewsky F, Matyash V, Wolf SA, Kettenmann H (2014) The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-ã, and IL-4. Glia 62(5):667-679.
15. Skaper SD, Giusti P, Facci L (2012) Microglia and mast cells: Two tracks on the road to neuroinflammation. FASEB J 26(8):3103-3117.
16. Theoharides TC, Valent P, Akin C (2015) Mast cells, mastocytosis, and related disorders. N Engl J Med 373(2):163-172.
17. Jang S, Kelley KW, Johnson RW (2008) Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA 105(21):7534-7539.
18. Li X, et al. (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207(1-2):111-116.
19. Ashwood P, et al. (2011) Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun 25(1):40-45.
20. Zimmerman AW, et al. (2005) Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 33(3):195-201.
21. Estes ML, McAllister AK (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16(8):469-486.
22. Young AM, et al. (2016) From molecules to neural morphology: Understanding neuroinflammation in autism spectrum condition. Mol Autism 7:9.
23. Hagberg H, Gressens P, Mallard C (2012) Inflammation during fetal and neonatal life: Implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 71(4):444-457.
24. Theoharides TC, Asadi S, Patel AB (2013) Focal brain inflammation and autism. J Neuroinflammation 10:46.
25. Theoharides TC, Stewart JM, Panagiotidou S, Melamed I (2015) Mast cells, brain inflammation and autism. Eur J Pharmacol 778:96-102.
26. Angelidou A, et al. (2010) Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation 7:48.
27. Tsilioni I, et al. (2014) Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Transl Psychiatry 4:e466.
28. Carraway R, Leeman SE (1973) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 248(19):6854-6861.
29. Dobner PR, Barber DL, Villa-Komaroff L, McKiernan C (1987) Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor. Proc Natl Acad Sci USA 84(10):3516-3520.
30. Vincent B, Vincent JP, Checler F (1994) Neurotensin and neuromedin N undergo distinct catabolic processes in murine astrocytes and primary cultured neurons. Eur J Biochem 221(1):297-306.
31. Navarro V, et al. (2001) Pharmacological properties of the mouse neurotensin receptor 3. Maintenance of cell surface receptor during internalization of neurotensin. FEBS Lett 495(1-2):100-105.
32. Chalon P, et al. (1996) Molecular cloning of a levocabastine-sensitive neurotensin binding site. FEBS Lett 386(2-3):91-94.
33. Mazella J, et al. (1996) Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain. J Neurosci 16(18):5613-5620.
34. Vincent JP, Mazella J, Kitabgi P (1999) Neurotensin and neurotensin receptors. Trends Pharmacol Sci 20(7):302-309.
35. Petersen CM, et al. (1997) Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J Biol Chem 272(6):3599-3605.
36. Hermans-Borgmeyer I, Hermey G, Nykjaer A, Schaller C (1999) Expression of the 100-kDa neurotensin receptor sortilin during mouse embryonal development. Brain Res Mol Brain Res 65(2):216-219.
37. Martin S, Dicou E, Vincent JP, Mazella J (2005) Neurotensin and the neurotensin receptor-3 in microglial cells. J Neurosci Res 81(3):322-326.
38. Smith AM, Dragunow M (2014) The human side of microglia. Trends Neurosci 37(3):125-135.
39. Seok J, et al.; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA 110(9):3507-3512.
40. Lee Y (2015) Roles of mTOR signaling in brain development. Exp Neurobiol 24(3):177-185.
41. Kwon CH, et al. (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50(3):377-388.
42. Wang H, Doering LC (2013) Reversing autism by targeting downstream mTOR signaling. Front Cell Neurosci 7:28.
43. Huber KM, Klann E, Costa-Mattioli M, Zukin RS (2015) Dysregulation of mammalian target of rapamycin signaling in mouse models of autism. J Neurosci 35(41):13836-13842.
44. Dello Russo C, Lisi L, Tringali G, Navarra P (2009) Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol 78(9):1242-1251.
45. Kim MS, Kuehn HS, Metcalfe DD, Gilfillan AM (2008) Activation and function of the mTORC1 pathway in mast cells. J Immunol 180(7):4586-4595.
46. Middleton E, Jr, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacol Rev 52(4):673-751.
47. Dirscherl K, et al. (2010) Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 7:3.
48. Kao TK, et al. (2011) Luteolin inhibits cytokine expression in endotoxin/cytokinestimulated microglia. J Nutr Biochem 22(7):612-624.
49. Zhu L, et al. (2014) Luteolin inhibits SH-SY5Y cell apoptosis through suppression of the nuclear transcription factor-êB, mitogen-activated protein kinase and protein kinase B pathways in lipopolysaccharide-stimulated cocultured BV2 cells. Exp Ther Med 7(5):1065-1070.
50. Parker-Athill E, et al. (2009) Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol 217(1-2):20-27.
51. Theoharides TC, Asadi S, Panagiotidou S (2012) A case series of a luteolin formulation (NeuroProtekβ) in children with autism spectrum disorders. Int J Immunopathol Pharmacol 25(2):317-323.
52. Taliou A, Zintzaras E, Lykouras L, Francis K (2013) An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin Ther 35(5):592-602.
53. Weng Z, Patel AB, Panagiotidou S, Theoharides TC (2015) The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol 135(4):1044-52.e5.
54. Walle T (2007) Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption. Mol Pharm 4(6):826-832.
55. Dicou E, Vincent JP, Mazella J (2004) Neurotensin receptor-3/sortilin mediates neurotensininduced cytokine/chemokine expression in a murine microglial cell line. J Neurosci Res 78(1):92-99.
56. Martin S, Vincent JP, Mazella J (2003) Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neurosci 23(4):1198-1205.
57. Masi A, et al. (2015) Cytokine aberrations in autism spectrum disorder: A systematic review and meta-analysis. Mol Psychiatry 20(4):440-446.
58. Tsilioni I, Taliou A, Francis K, Theoharides TC (2015) Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6. Transl Psychiatry 5:e647.
59. Choi GB, et al. (2016) The maternal interleukin-17a pathway in mice promotes autismlike phenotypes in offspring. Science 351(6276):933-939.
60. Ito D, et al. (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 57(1):1-9.
61. Navarro V, Vincent JP, Mazella J (2002) Shedding of the luminal domain of the neurotensin receptor-3/sortilin in the HT29 cell line. Biochem Biophys Res Commun 298(5):760-764.
62. Hannum CH, et al. (1990) Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343(6256):336-340.
63. Butler MG, et al. (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42(4):318-321.
64. Varga EA, Pastore M, Prior T, Herman GE, McBride KL (2009) The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med 11(2):111-117.
65. Costa-Mattioli M, Monteggia LM (2013) mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 16(11):1537-1543.
66. Kassai H, et al. (2014) Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative diseases. Cell Reports 7(5):1626-1639.
67. Dan HC, et al. (2008) Akt-dependent regulation of NF-kappaB is controlled by mTOR and Raptor in association with IKK. Genes Dev 22(11):1490-1500.
68. Saleiro D, Platanias LC (2015) Intersection of mTOR and STAT signaling in immunity. Trends Immunol 36(1):21-29.
69. Weichhart T, et al. (2008) The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29(4):565-577.
70. Park JS, et al. (2007) Anti-inflammatory mechanisms of isoflavone metabolites in lipopolysaccharide-stimulated microglial cells. J Pharmacol Exp Ther 320(3):1237-1245.
71. Yang Y, et al. (2013) Polyphenols differentially inhibit degranulation of distinct subsets of vesicles in mast cells by specific interaction with granule-type-dependent SNARE complexes. Biochem J 450(3):537-546.
72. Yang Y, et al. (2015) Dynamic light scattering analysis of SNARE-driven membrane fusion and the effects of SNARE-binding flavonoids. Biochem Biophys Res Commun 465(4):864-870.
73. Carraway RE, Mitra SP, Evers BM, Townsend CM, Jr (1994) BON cells display the intestinal pattern of neurotensin/neuromedin N precursor processing. Regul Pept 53(1):17-29.
74. Castagliuolo I, et al. (1999) Neurotensin is a proinflammatory neuropeptide in colonic inflammation. J Clin Invest 103(6):843-849.
75. Miller LA, Cochrane DE, Carraway RE, Feldberg RS (1995) Blockade of mast cell histamine secretion in response to neurotensin by SR 48692, a nonpeptide antagonist of the neurotensin brain receptor. Br J Pharmacol 114(7):1466-1470.
76. Donelan J, et al. (2006) Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci USA 103(20):7759-7764.
77. Wallon C, et al. (2008) Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro. Gut 57(1):50-58.
78. Theoharides TC, Doyle R (2008) Autism, gut-blood-brain barrier, and mast cells. J Clin Psychopharmacol 28(5):479-483.
79. Theoharides TC (1990) Mast cells: The immune gate to the brain. Life Sci 46(9):607-617.
80. Esposito P, et al. (2002) Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther 303(3):1061-1066.
81. Ribatti D (2015) The crucial role of mast cells in blood-brain barrier alterations. Exp Cell Res 338(1):119-125.
82. Theoharides TC, Weinkauf C, Conti P (2004) Brain cytokines and neuropsychiatric disorders. J Clin Psychopharmacol 24(6):577-581.
83. Takeshita Y, Ransohoff RM (2012) Inflammatory cell trafficking across the blood-brain barrier: Chemokine regulation and in vitro models. Immunol Rev 248(1):228-239.
84. Rochfort KD, Cummins PM (2015) The blood-brain barrier endothelium: A target for pro-inflammatory cytokines. Biochem Soc Trans 43(4):702-706.
85. Dong H, et al. (2014) Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. Mol Neurobiol 49(3):1487-1500.
86. Zhang S, Zeng X, Yang H, Hu G, He S (2012) Mast cell tryptase induces microglia activation via protease-activated receptor 2 signaling. Cell Physiol Biochem 29(5-6):931-940.
87. Skaper SD, Facci L, Giusti P (2014) Mast cells, glia and neuroinflammation: Partners in crime? Immunology 141(3):314-327.
88. Gupta S, et al. (2014) Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 5:5748.
89. Theoharides TC, Tsilioni I, Patel AB, Doyle R (2016) Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry 6(6):e844.
90. Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci USA 109(31):12776-12781.
91. Garay PA, Hsiao EY, Patterson PH, McAllister AK (2013) Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun 31:54-68.
92. Li J, Kim SG, Blenis J (2014) Rapamycin: One drug, many effects. Cell Metab 19(3):373-379.
93. Wander SA, Hennessy BT, Slingerland JM (2011) Next-generation mTOR inhibitors in clinical oncology: How pathway complexity informs therapeutic strategy. J Clin Invest 121(4):1231-1241.
94. Ghosh A, Michalon A, Lindemann L, Fontoura P, Santarelli L (2013) Drug discovery for autism spectrum disorder: challenges and opportunities. Nat Rev Drug Discov 12(10):777-790.