1. Guanabenz inhibits TLR9 signaling through a pathway that is independent of eIF2α dephosphorylation by the GADD34/PP1c complex
- Author
-
Alexandre Dalet, Manuel A. S. Santos, Jessica Perego, Thien-Phong Vu Manh, Evelina Gatti, Alexis J. Combes, Lionel Spinelli, Nathalie Bardin, Clarisse Bourbon, Laurent Chiche, Andreia Mendes, Lionel Chasson, Philippe Pierre, Voahirana Camosseto, Hong Liu, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen [Fondation Ambroise Paré - Marseille], Institute for Research in Biomedicine ( iBiMED), Universidade de Aveiro, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)
- Subjects
Male ,0301 basic medicine ,CpG Oligodeoxynucleotide ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Eukaryotic Initiation Factor-2 ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biochemistry ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Protein Phosphatase 1 ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Phosphorylation ,Molecular Biology ,Antihypertensive Agents ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Guanabenz ,Chemistry ,Liver Diseases ,Endoplasmic reticulum ,TLR9 ,Dendritic Cells ,Cell Biology ,Endoplasmic Reticulum Stress ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Cytokine ,Gene Expression Regulation ,Toll-Like Receptor 9 ,030220 oncology & carcinogenesis ,Unfolded protein response ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,medicine.drug - 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. published
- Published
- 2018
- Full Text
- View/download PDF