Aryl hydrocarbon receptor in the control of innate immune responses during inflammatory autoimmune diseases of the central nervous system

• Applicant: Professor Dr. Veit Rothhammer
• Subject Area: Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258867603

• Final Report Year: 2018

Final Report Abstract

Multiple Sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system (CNS), in which a complex interplay between CNS resident glial cells and brain infiltrating immune cells causes inflammatory lesions in the CNS, which ultimately lead to neurodegeneration and accumulation of neurologic deficits. Environmental factors potently influence induction and maintenance of inflammatory processes, but need to interact with defined ligand-specific receptors. Activation of the Aryl hydrocarbon receptor (AHR), a intracellular receptor for endogenous and environmental ligands, dampens immune responses in the adaptive immune system by down-modulating not only pathogenic T cell responses. However, its role in CNS resident glial cells is largely unknown. In the projects carried out under support of the German research foundation, we have been able to show that both astrocytes and microglia control acute and chronic stages of MS and EAE via AHR. Indeed, in a first project, we defined AHR and Type I interferon signaling in astrocytes as molecular mediators inducing down-modulatory pathways controlled by NF-κB. Deprivation of metabolic AHR ligands or AHR in astrocytes lead to exacerbated forms of EAE and MS. Thus, determining AHR agonistic activity in biological samples is of relevance for autoimmune diseases including MS, rheumatoid arthritis, and inflammatory bowel disease. We have outlined in a second project the conditions necessary for accurate measurement of AHR ligand net activity in biological samples. In a third translational project, we have defined S1PR signaling as a potential target for modulating astrocyte activity during inflammatory diseases of the CNS. Finally, we have used transgenic mouse models with conditional deletion of AHR in microglia to define novel positive and negative regulators governing astrocyte polarization in EAE and MS. Taken together, we have defined novel mechanisms under control of AHR in CNS resident glial cells, which may guide future approaches to develop therapeutic targets for MS and other autoimmune inflammatory diseases. The fruitful and rewarding experience made possible by the German research foundation has led to meaningful scientific results and will guide my future scientific endeavors.

Publications

• (2016) Astrocyte-intrinsic regulation of central nervous system inflammation and neurodegeneration. Clin Exp Neuroimmunol (Clinical and Experimental Neuroimmunology) 7 (1) 28–38
  Rothhammer, Veit; Quintana, Francisco J.
  
• (2018) Microglial control of astrocytes in response to microbial metabolites. Nature 557 (7707) 724–728
  Rothhammer, Veit; Borucki, Davis M.; Tjon, Emily C.; Takenaka, Maisa C.; Chao, Chun-Cheih; Ardura-Fabregat, Alberto; Lima, Kalil Alves de; Gutiérrez-Vázquez, Cristina; Hewson, Patrick; Staszewski, Ori; Blain, Manon; Healy, Luke; Neziraj, Tradite; Borio, M
  
• (2015). Control of autoimmune CNS inflammation by astrocytes. Semin. Immunopathol. 2015 Nov;37(6):625-38
  Rothhammer V, Quintana FJ
  
• Role of astrocytes and microglia in central nervous system inflammation. Introduction. Semin Immunopathol. 2015 Nov;37(6):575-6
  Rothhammer V, Quintana FJ
  
• (2016). Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nature Medicine, 2016
  Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kebir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ
  
• Environmental control of autoimmune inflammation in the central nervous system. Curr Opin Immunol. 2016 Dec;43:46-53
  Rothhammer V, Quintana FJ
  
• (2017). Dynamic regulation of serum aryl hydrocarbon receptor agonists in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm July 2017 vol. 4 no. 4 e359
  Rothhammer V, Borucki DM, Garcia Sanchez MI, Mazzola MA, Hemond CC, Regev K, Paul A, Kivisäkk P, Bakshi R, Izquierdo G, Weiner HL, and Quintana FJ
  
• Control of immune-mediated pathology via the aryl hydrocarbon receptor. J Biol Chem. 2017 Jul 28;292(30):12383-12389
  Wheeler MA, Rothhammer V, Quintana FJ
  
• Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci USA. 2017 Feb 21;114(8):2012-2017
  Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A, Blain M, Healy L, Antel J, Quintana FJ
  
• Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep. 2018 Mar 21;8(1):4970
  Rothhammer V, Borucki DM, Kenison JE, Hewson P, Wang Z, Bakshi R, Sherr DH, Quintana FJ