PMID- 36232593
OWN - NLM
STAT- MEDLINE
DCOM- 20221017
LR  - 20221019
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 19
DP  - 2022 Sep 25
TI  - Targeting Signaling Pathway Downstream of RIG-I/MAVS in the CNS Stimulates 
      Production of Endogenous Type I IFN and Suppresses EAE.
LID - 10.3390/ijms231911292 [doi]
LID - 11292
AB  - Type I interferons (IFN), including IFNbeta, play a protective role in multiple 
      sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis 
      (EAE). Type I IFNs are induced by the stimulation of innate signaling, including 
      via cytoplasmic RIG-I-like receptors. In the present study, we investigated the 
      potential effect of a chimeric protein containing the key domain of RIG-I 
      signaling in the production of CNS endogenous IFNbeta and asked whether this would 
      exert a therapeutic effect against EAE. We intrathecally administered an 
      adeno-associated virus vector (AAV) encoding a fusion protein comprising RIG-I 
      2CARD domains (C) and the first 200 amino acids of mitochondrial 
      antiviral-signaling protein (MAVS) (M) (AAV-CM). In vivo imaging in 
      IFNbeta/luciferase reporter mice revealed that a single intrathecal injection of 
      AAV-CM resulted in dose-dependent and sustained IFNbeta expression within the CNS. 
      IFNbeta expression was significantly increased for 7 days. Immunofluorescent 
      staining in IFNbeta-YFP reporter mice revealed extraparenchymal CD45+ cells, choroid 
      plexus, and astrocytes as sources of IFNbeta. Moreover, intrathecal administration 
      of AAV-CM at the onset of EAE induced the suppression of EAE, which was 
      IFN-I-dependent. These findings suggest that accessing the signaling pathway 
      downstream of RIG-I represents a promising therapeutic strategy for inflammatory 
      CNS diseases, such as MS.
FAU - Kronborg Hansen, Anne K
AU  - Kronborg Hansen AK
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
FAU - Dubik, Magdalena
AU  - Dubik M
AUID- ORCID: 0000-0002-4521-0410
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
FAU - Marczynska, Joanna
AU  - Marczynska J
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
FAU - Ojha, Bhavya
AU  - Ojha B
AUID- ORCID: 0000-0003-4919-6836
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
FAU - Nistal-Villan, Estanislao
AU  - Nistal-Villan E
AUID- ORCID: 0000-0003-2458-8833
AD  - Microbiology Section, Department of Pharmaceutical and Health Science, Faculty of 
      Pharmacy, University CEU San Pablo, Campus Monteprincipe, 28003 Madrid, Spain.
FAU - Gonzalez Aseguinolaza, Gloria
AU  - Gonzalez Aseguinolaza G
AUID- ORCID: 0000-0002-1600-4562
AD  - Gene Therapy and Regulation of Gene Expression Program, Center for Applied 
      Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
AD  - IdiSNA Navarra Institute for Health Research, 31008 Pamplona, Spain.
FAU - Arengoth, Dina S
AU  - Arengoth DS
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
FAU - Owens, Trevor
AU  - Owens T
AUID- ORCID: 0000-0001-9315-6036
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
FAU - Khorooshi, Reza
AU  - Khorooshi R
AD  - Department of Neurobiology Research, Institute of Molecular Medicine, University 
      of Southern Denmark, 5000 Odense, Denmark.
LA  - eng
GR  - (DFF, 4183-00198A and 8020- 00157B)/Independent Research Fund Denmark/
GR  - the Danish Multiple Sclerosis Society/the Danish Multiple Sclerosis Society/
GR  - Lundbeckfonden/Lundbeckfonden/
GR  - (ECTRIMS)/The European Committee for Treatment and Research in Multiple Sclerosis 
      (ECTRIMS) Postdoctoral Research Fellowship Programme/
GR  - A.P. Moller Fonden/A.P. Moller Fonden/
GR  - Direktor Ejnar Jonasson kaldet Johnsen og hustrus mindelegat/Direktor Ejnar 
      Jonasson kaldet Johnsen og hustrus mindelegat/
GR  - EU.MSCA ITN PMSMatTrain/EU.MSCA ITN PMSMatTrain/
PT  - Journal Article
DEP - 20220925
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Amino Acids)
RN  - 0 (Antiviral Agents)
RN  - 0 (Interferon Type I)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 77238-31-4 (Interferon-beta)
SB  - IM
MH  - Amino Acids
MH  - Animals
MH  - Antiviral Agents
MH  - *Encephalomyelitis, Autoimmune, Experimental/drug therapy
MH  - *Interferon Type I/metabolism
MH  - Interferon-beta/genetics/metabolism
MH  - Mice
MH  - Recombinant Fusion Proteins
MH  - Signal Transduction
PMC - PMC9570082
OTO - NOTNLM
OT  - 2CARD-MAVS200
OT  - MAVS
OT  - RIG-I
OT  - experimental autoimmune encephalomyelitis
OT  - type I interferon
COIS- The authors declare that they have no competing interest.
EDAT- 2022/10/15 06:00
MHDA- 2022/10/18 06:00
PMCR- 2022/09/25
CRDT- 2022/10/14 02:08
PHST- 2022/08/25 00:00 [received]
PHST- 2022/09/19 00:00 [revised]
PHST- 2022/09/22 00:00 [accepted]
PHST- 2022/10/14 02:08 [entrez]
PHST- 2022/10/15 06:00 [pubmed]
PHST- 2022/10/18 06:00 [medline]
PHST- 2022/09/25 00:00 [pmc-release]
AID - ijms231911292 [pii]
AID - ijms-23-11292 [pii]
AID - 10.3390/ijms231911292 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Sep 25;23(19):11292. doi: 10.3390/ijms231911292.