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Sci Signal. 2018 Jan 23;11(514). pii: eaam8104. doi: 10.1126/scisignal.aam8104.

Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex.

Author information

1
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13008 Marseille, France.
2
International Associated Laboratory (LIA) CNRS "Mistra," 13008 Marseille, France.
3
Sanofi, Cambridge, MA 02139, USA.
4
Laboratoire d'Immunologie, Hôpital de la Conception, 13005 Marseille, France.
5
Aix Marseille Université, INSERM, VRCM, 13005 Marseille, France.
6
Hôpital Européen, 13003 Marseille, France.
7
Institute for Research in Biomedicine (iBiMED) and Aveiro Health Sciences Program University of Aveiro, 3810-193 Aveiro, Portugal.
8
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13008 Marseille, France. gatti@ciml.univ-mrs.fr pierre@ciml.univ-mrs.fr.

Abstract

Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, guanabenz protected mice from CpG oligonucleotide-dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that guanabenz and similar compounds could be used to treat type I IFN-dependent pathologies and that CH25H could be a therapeutic target to control these diseases.

PMID:
29363586
DOI:
10.1126/scisignal.aam8104

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