AhR-deficiency as a cause of demyelinating disease and inflammation
Ludmila Juricek, Julie Carcaud, Alice Pelhaitre, Thorfinn T Riday, Aline Chevallier, Justine Lanzini, Nicolas Auzeil, Olivier Laprévote, Florent Dumont, Sebastien Jacques, Frank Letourneur, Charbel Massaad, Cendra Agulhon, Robert Barouki, Mathieu Beraneck, Xavier Coumoul, Ludmila Juricek, Julie Carcaud, Alice Pelhaitre, Thorfinn T Riday, Aline Chevallier, Justine Lanzini, Nicolas Auzeil, Olivier Laprévote, Florent Dumont, Sebastien Jacques, Frank Letourneur, Charbel Massaad, Cendra Agulhon, Robert Barouki, Mathieu Beraneck, Xavier Coumoul
Abstract
The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.
Conflict of interest statement
The authors declare that they have no competing interests.
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References
- Barouki R, Coumoul X, Fernandez-Salguero PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett. 2007;581:3608–3615. doi: 10.1016/j.febslet.2007.03.046.
- Choudhary, M. et al. Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways. J. Pathol., doi:10.1002/path.4433 (2014).
- Mulero-Navarro S, Fernandez-Salguero PM. New Trends in Aryl Hydrocarbon Receptor Biology. Front. Cell Dev. Biol. 2016;4 doi: 10.3389/fcell.2016.00045.
- Abbott BD, Birnbaum LS, Perdew GH. Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo. Dev. Dyn. Off. Publ. Am. Assoc. Anat. 1995;204:133–143.
- Williamson MA, Gasiewicz TA, Opanashuk LA. Aryl hydrocarbon receptor expression and activity in cerebellar granule neuroblasts: implications for development and dioxin neurotoxicity. Toxicol. Sci. Off. J. Soc. Toxicol. 2005;83:340–348. doi: 10.1093/toxsci/kfi031.
- Latchney SE, Hein AM, O’Banion MK, DiCicco-Bloom E, Opanashuk LA. Deletion or activation of the aryl hydrocarbon receptor alters adult hippocampal neurogenesis and contextual fear memory. J. Neurochem. 2013;125:430–445. doi: 10.1111/jnc.12130.
- Petersen SL, et al. Distribution of mRNAs encoding the arylhydrocarbon receptor, arylhydrocarbon receptor nuclear translocator, and arylhydrocarbon receptor nuclear translocator-2 in the rat brain and brainstem. J. Comp. Neurol. 2000;427:428–439. doi: 10.1002/1096-9861(20001120)427:3<428::AID-CNE9>;2-P.
- Filbrandt CR, Wu Z, Zlokovic B, Opanashuk L, Gasiewicz TA. Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes. Neurotoxicology. 2004;25:605–616. doi: 10.1016/j.neuro.2003.08.007.
- Chevallier A, et al. Oculomotor deficits in aryl hydrocarbon receptor null mouse. PloS One. 2013;8 doi: 10.1371/journal.pone.0053520.
- Richards MD, Wong A. Infantile nystagmus syndrome: clinical characteristics, current theories of pathogenesis, diagnosis, and management. Can. J. Ophthalmol. J. Can. Ophtalmol. 2015;50:400–408. doi: 10.1016/j.jcjo.2015.07.010.
- Yonehara K, et al. Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity. Neuron. 2016;89:177–193. doi: 10.1016/j.neuron.2015.11.032.
- Trobe JD, Sharpe JA, Hirsh DK, Gebarski SS. Nystagmus of Pelizaeus-Merzbacher disease. A magnetic search-coil study. Arch. Neurol. 1991;48:87–91. doi: 10.1001/archneur.1991.00530130099026.
- Hickman SJ, Raoof N, McLean RJ, Gottlob I. Vision and multiple sclerosis. Mult. Scler. Relat. Disord. 2014;3:3–16. doi: 10.1016/j.msard.2013.04.004.
- Leigh, R. J. & Zee, D. S. The Neurology of Eye Movements. (Oxford University Press, 2015).
- Beraneck, M., Lambert, F. M. & Sadeghi, S. G. Functional development of rodent vestibular system: sensorimotor pathways for stabilization of gaze and posture. In R. Romand & I. Varela-Nieto (Eds), Development of Auditory and Vestibular Systems: Academic Press 449–488 (Academic Press, 2014).
- Rick JM, Horschke I, Neuhauss SC. Optokinetic behavior is reversed in achiasmatic mutant zebrafish larvae. Curr. Biol. CB. 2000;10:595–598. doi: 10.1016/S0960-9822(00)00495-4.
- Huang Y-Y, Rinner O, Hedinger P, Liu S-C, Neuhauss SCF. Oculomotor instabilities in zebrafish mutant belladonna: a behavioral model for congenital nystagmus caused by axonal misrouting. J. Neurosci. Off. J. Soc. Neurosci. 2006;26:9873–9880. doi: 10.1523/JNEUROSCI.2886-06.2006.
- Williams RW, Hogan D, Garraghty PE. Target recognition and visual maps in the thalamus of achiasmatic dogs. Nature. 1994;367:637–639. doi: 10.1038/367637a0.
- Long M, Jiang W, Liu D, Yao H. Contrast-dependent orientation discrimination in the mouse. Sci. Rep. 2015;5 doi: 10.1038/srep15830.
- Barton JJ, Cox TA, Digre KB. Acquired convergence-evoked pendular nystagmus in multiple sclerosis. J. Neuro-Ophthalmol. Off. J. North Am. Neuro-Ophthalmol. Soc. 1999;19:34–38.
- Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 2001;81:871–927.
- Wang Y, Wu TR, Cai S, Welte T, Chin YE. Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation. Mol. Cell. Biol. 2000;20:4505–4512. doi: 10.1128/MCB.20.13.4505-4512.2000.
- Fernández M, et al. A single prenatal exposure to the endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin alters developmental myelination and remyelination potential in the rat brain. J. Neurochem. 2010;115:897–909. doi: 10.1111/j.1471-4159.2010.06974.x.
- Mayo L, et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 2014;20:1147–1156. doi: 10.1038/nm.3681.
- Quintana FJ, et al. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453:65–71. doi: 10.1038/nature06880.
- Huai W, et al. Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nat. Commun. 2014;5 doi: 10.1038/ncomms5738.
- Kimura A, et al. Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J. Exp. Med. 2009;206:2027–2035. doi: 10.1084/jem.20090560.
- Li J, Parker B, Martyn C, Natarajan C, Guo J. The PMP22 gene and its related diseases. Mol. Neurobiol. 2013;47:673–698. doi: 10.1007/s12035-012-8370-x.
- Lossos A, et al. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain J. Neurol. 2015;138:2521–2536. doi: 10.1093/brain/awv204.
- Fernandez-Salguero P, et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 1995;268:722–726. doi: 10.1126/science.7732381.
- Launay, P.-S. et al. Combined 3DISCO clearing method, retrograde tracer and ultramicroscopy to map corneal neurons in a whole adult mouse trigeminal ganglion. Exp. Eye Res., doi:10.1016/j.exer.2015.06.008 (2015).
- Ertürk A, et al. Three-dimensional imaging of solvent-cleared organs using 3DISCO. Nat. Protoc. 2012;7:1983–1995. doi: 10.1038/nprot.2012.119.
- Tomkiewicz C, et al. The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway. Oncogene. 2013;32:1811–1820. doi: 10.1038/onc.2012.197.
- Bolstad BM, Irizarry RA, Astrand M, Speed TP. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinforma. Oxf. Engl. 2003;19:185–193. doi: 10.1093/bioinformatics/19.2.185.
- Kaye, J. et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA, doi:10.1073/pnas.1607843113 (2016).
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