Journal of Neuroinflammation | |
The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages | |
Nicola Antonucci2  Alessandra Cirillo3  James Jeffrey Bradstreet1  Dario Siniscalco4  | |
[1] Western University of Health Science, 309 E. Second St., Pomona, CA 91766, USA;Biomedical Center for Autism Research and Treatment, Bari 70126, Italy;Institute of Bioscience and Bioresources, National Research Council of Italy, Naples 80128, Italy;Cancellautismo- no profit association for autism care, Florence 50132, Italy | |
关键词: Autism; Macrophages; Gene expression; Endocannabinoids; GcMAF; | |
Others : 804601 DOI : 10.1186/1742-2094-11-78 |
|
received in 2014-03-12, accepted in 2014-04-02, 发布年份 2014 | |
【 摘 要 】
Background
Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls.
Methods
To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods.
Results
GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children.
Conclusions
This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.
【 授权许可】
2014 Siniscalco et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20140708063544360.pdf | 1389KB | download | |
20140713211203636.pdf | 323KB | download | |
Figure 5. | 43KB | Image | download |
Figure 4. | 105KB | Image | download |
Figure 3. | 41KB | Image | download |
Figure 2. | 44KB | Image | download |
Figure 1. | 155KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
【 参考文献 】
- [1]American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Text Revision. 4th edition. Washington, DC, USA: American Psychiatric Association; 2000.
- [2]Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N: Epigenetic findings in autism: new perspectives for therapy. Int J Environ Res Public Health 2013, 10(9):4261-4273.
- [3]Siniscalco D: Current findings and research prospective in autism spectrum disorders. Autism 2013, S2:e001.
- [4]Siniscalco D, Cubala-Kucharska M: Treatment of the child with autism-newest medical trends. Autism 2013, 3:110.
- [5]Siniscalco D, Sapone A, Cirillo A, Giordano C, Maione S, Antonucci N: Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? J Biomed Biotechnol 2012, 2012:480289.
- [6]Lyall K, Ashwood P, Van de Water J, Hertz-Picciotto I: Maternal immune-mediated conditions, autism spectrum disorders, and developmental delay. J Autism Dev Disord 2013. Epub ahead of print
- [7]Siniscalco D, Bradstreet JJ, Antonucci N: Therapeutic role of hematopoietic stem cells in autism spectrum disorder-related inflammation. Front Immunol 2013, 4:140.
- [8]Onore C, Careaga M, Ashwood P: The role of immune dysfunction in the pathophysiology of autism. Brain BehavImmun 2012, 26(3):383-392.
- [9]Siniscalco D, Sapone A, Giordano C, Cirillo A, de Novellis V, de Magistris L, Rossi F, Fasano A, Maione S, Antonucci N: The expression of caspases is enhanced in peripheral blood mononuclear cells of autism spectrum disorder patients. J Autism Dev Disord 2012, 42(7):1403-1410.
- [10]Gesundheit B, Rosenzweig JP, Naor D, Lerer B, Zachor DA, Procházka V, Melamed M, Kristt DA, Steinberg A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA, Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P: Immunological and autoimmune considerations of Autism Spectrum Disorders. J Autoimmun 2013, 44:1-7.
- [11]Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG: Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry 2013, 3:e278.
- [12]DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC: Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol 2013, 39(5):458-484.
- [13]Ota K, Dambaeva S, Han AR, Beaman K, Gilman-Sachs A, Kwak-Kim J: Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity. Hum Reprod 2014, 29(2):208-219.
- [14]Fletcher JM, Basdeo SA, Allen AC, Dunne PJ: Therapeutic use of vitamin D and its analogues in autoimmunity. Recent Pat Inflamm Allergy Drug Discov 2012, 6(1):22-34.
- [15]Cannell JJ, Grant WB: What is the role of vitamin D in autism? Dermatoendocrinol 2013, 5(1):199-204.
- [16]Bradstreet JJ, Vogelaar E, Thyer L: Initial observations of elevated alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from Gcprotein-Macrophage Activating Factor injections. Autism Insights 2012, 4:31-38.
- [17]Yamamoto N, Naraparaju VR: Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor. Cancer Res 1997, 57(11):2187-2192.
- [18]Yamamoto N, Naraparaju VR, Moore M, Brent LH: Deglycosylation of serum vitamin D3-binding protein by alpha-N-acetylgalactosaminidase detected in the plasma of patients with systemic lupus erythematosus. Clin Immunol Immunopathol 1997, 82(3):290-298.
- [19]Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, Fasano A, Bradstreet JJ, Maione S, Antonucci N: Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord 2013, 43(11):2686-2695.
- [20]Ahmad R, Koole M, Evens N, Serdons K, Verbruggen A, Bormans G, Van Laere K: Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol Imaging Biol 2013, 15(4):384-390.
- [21]Zarruk JG, Fernández-López D, García-Yébenes I, García-Gutiérrez MS, Vivancos J, Nombela F, Torres M, Burguete MC, Manzanares J, Lizasoain I, Moro MA: Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 2012, 43(1):211-219.
- [22]Pacher P, Bátkai S, Kunos G: The EC system as an emerging target of pharmacotherapy. Pharmacol Rev 2006, 58(3):389-462.
- [23]Lord C, Rutter M, Le Couteur A: Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994, 24(5):659-685.
- [24]Schopler E, Reichler RJ, Renner BR: The Childhood Autism Rating Scale (CARS). Los Angeles, CA: Western Psychological Services; 1993.
- [25]Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M: The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000, 30(3):205-223.
- [26]Rossi F, Siniscalco D, Luongo L, De Petrocellis L, Bellini G, Petrosino S, Torella M, Santoro C, Nobili B, Perrotta S, Di Marzo V, Maione S: The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone 2009, 44(3):476-484.
- [27]Crespo H, Reina R, Glaria I, Ramírez H, de Andrés X, Jáuregui P, Luján L, Martínez-Pomares L, Amorena B, de Andrés DF: Identification of the ovine mannose receptor and its possible role in Visna/Maedi virus infection. Vet Res 2011, 42:28. BioMed Central Full Text
- [28]Pacini S, Morucci G, Punzi T, Gulisano M, Ruggiero M: Gc protein-derived macrophage-activating factor (GcMAF) stimulates cAMP formation in human mononuclear cells and inhibits angiogenesis in chick embryo chorionallantoic membrane assay. Cancer Immunol Immunother 2011, 60(4):479-485.
- [29]Stamova BS, Apperson M, Walker WL, Tian Y, Xu H, Adamczy P, Zhan X, Liu DZ, Ander BP, Liao IH, Gregg JP, Turner RJ, Jickling G, Lit L, Sharp FR: Identification and validation of suitable endogenous reference genes for gene expression studies in human peripheral blood. BMC Med Genomics 2009, 2:49. BioMed Central Full Text
- [30]Bradford MM: A rapid and sensitive method for the quantization of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248-254.
- [31]Li R, Shen Y: An old method facing a new challenge: re-visiting housekeeping proteins as internal reference control for neuroscience research. Life Sci 2013, 92(13):747-751.
- [32]Giordano C, Siniscalco D, Melisi D, Luongo L, Curcio A, Soukupova M, Palazzo E, Marabese I, De Chiaro M, Rimoli MG, Rossi F, Maione S, de Novellis V: The galactosylation of N (ω)-nitro-L-arginine enhances its anti-nocifensive or anti-allodynic effects by targeting glia in healthy and neuropathic mice. Eur J Pharmacol 2011, 656(1–3):52-62.
- [33]Ardura JA, Friedman PA: Regulation of G protein-coupled receptor function by Na+/H + exchange regulatory factors. Pharmacol Rev 2011, 63(4):882-900.
- [34]Peralta L, Agirregoitia E, Mendoza R, Expósito A, Casis L, Matorras R, Agirregoitia N: Expression and localization of cannabinoid receptors in human immature oocytes and unfertilized metaphase-II oocytes. Reprod Biomed Online 2011, 23(3):372-379.
- [35]Van Camp JK, Beckers S, Zegers D, Van Hul W: Wnt signaling and the control of human stem cell fate. Stem Cell Rev 2014, 10(2):207-229.
- [36]Boonyatecha N, Sangphech N, Wongchana W, Kueanjinda P, Palaga T: Involvement of Notch signaling pathway in regulating IL-12 expression via c-Rel in activated macrophages. Mol Immunol 2012, 51(3–4):255-262.
- [37]Zhang Y, Yuan X, Wang Z, Li R: The canonical Wntsignaling pathway in autism. CNS NeurolDisord Drug Targets 2013. [Epub ahead of print]
- [38]Haase J, Weyer U, Immig K, Klöting N, Blüher M, Eilers J, Bechmann I, Gericke M: Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia 2014, 57(3):562-71.
- [39]Kittan NA, Allen RM, Dhaliwal A, Cavassani KA, Schaller M, Gallagher KA, Carson WF 4th, Mukherjee S, Grembecka J, Cierpicki T, Jarai G, Westwick J, Kunkel SL, Hogaboam CM: Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes. PLoS One 2013, 8(10):e78045.
- [40]Siniscalco D, Giordano C, Galderisi U, Luongo L, de Novellis V, Rossi F, Maione S: Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic mice. Front Integr Neurosci 2011, 5:79.
- [41]Yamamoto N, Willett NP, Lindsay DD: Participation of serum proteins in the inflammation-primed activation of macrophages. Inflammation 1994, 18(3):311-322.
- [42]Nonaka K, Onizuka S, Ishibashi H, Uto Y, Hori H, Nakayama T, Matsuura N, Kanematsu T, Fujioka H: Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice. J Surg Res 2012, 172(1):116-122.
- [43]Yamamoto N, Suyama H, Yamamoto N: Immunotherapy for prostate cancer with Gcprotein-derived Macrophage-Activating Factor. GcMAF TranslOncol 2008, 1(2):65-72.
- [44]Kanda S, Mochizuki Y, Miyata Y, Kanetake H, Yamamoto N: Effects of vitamin D (3)-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis. J Natl Cancer Inst 2002, 94(17):1311-1319.
- [45]Solinas M, Massi P, Cantelmo AR, Cattaneo MG, Cammarota R, Bartolini D, Cinquina V, Valenti M, Vicentini LM, Noonan DM, Albini A, Parolaro D: Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol 2012, 167(6):1218-1231.
- [46]Xu J, Li W, Ma J, Liu J, Sha H, Zhou S, Wang F, Ma Q: Vitamin D - pivotal nutraceutical in the regulation of cancer metastasis and angiogenesis. Curr Med Chem 2013, 20(33):4109-4120.
- [47]Pacini S, Morucci G, Punzi T, Gulisano M, Ruggiero M, Amato M, Aterini S: Effect of paricalcitol and GcMAF on angiogenesis and human peripheral blood mononuclear cell proliferation and signaling. J Nephrol 2012, 25(4):577-581.
- [48]Bakare MO, Munir KM, Kinney DK: Association of hypomelanotic skin disorders with autism: links to possible etiologic role of vitamin-D levels in autism? Hypothesis (Tor) 2011, 9(1):e2.
- [49]Mostafa GA, Al-Ayadhi LY: Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. J Neuroinflammation 2012, 9:201. BioMed Central Full Text
- [50]Yamamoto N, Naraparaju VR, Asbell SO: Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in cancer patients. Cancer Res 1996, 56(12):2827-2831.
- [51]Börner C, Smida M, Höllt V, Schraven B, Kraus J: Cannabinoid receptor type 1- and 2-mediated increase in cyclic AMP inhibits T cell receptor-triggered signaling. J BiolChem 2009, 284(51):35450-35460.
- [52]Zheng C, Chen L, Chen X, He X, Yang J, Shi Y, Zhou N: The second intracellular loop of the human cannabinoid CB2 receptor governs G protein coupling in coordination with the carboxyl terminal domain. PLoS One 2013, 8(5):e63262. doi:10.1371/journal.pone.0063262
- [53]Al-Ayadhi LY: Pro-inflammatory cytokines in autistic children in central Saudi Arabia. Neurosciences (Riyadh) 2005, 10(2):15515-15518.
- [54]Siniscalco D, Antonucci N: Possible use of Trichurissuis ova in autism spectrum disorders therapy. Med Hypotheses 2013, 81(1):1-4.
- [55]Al-Ayadhi LY, Mostafa GA: Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children. J Neuroinflammation 2013, 10:72. BioMed Central Full Text
- [56]Molloy CA, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K, Manning-Courtney P, Altaye M, Wills-Karp M: Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 2006, 172(1–2):198-205.
- [57]Hume DA: Macrophages as APC and the dendritic cell myth. J Immunol 2008, 181:5829-5835.
- [58]Piras IS, Haapanen L, Napolioni V, Sacco R, Van de Water J, Persico AM: Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder. Brain Behav Immun 2014, 38:91-99.
- [59]Hornig M: The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Curr Opin Rheumatol 2013, 25(4):488-795.
- [60]De Theije CG, Wopereis H, Ramadan M, van Eijndthoven T, Lambert J, Knol J, Garssen J, Kraneveld AD, Oozeer R: Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun 2014, 37:197-206.
- [61]Wood JT, Williams JS, Pandarinathan L, Janero DR, Lammi-Keefe CJ, Makriyannis A: Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma. J Lipid Res 2010, 51(6):1416-1423.
- [62]Artmann A, Petersen G, Hellgren LI, Boberg J, Skonberg C, Nellemann C, Hansen SH, Hansen HS: Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta 2008, 1781(4):200-212.