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

Guanabenz attenuates autoimmune inflammation by preventing TLR9 from reaching endosomes and becoming fully activated. From fighting hypertension to inflammation The FDA-approved antihypertensive drug guanabenz also has anti-inflammatory properties, which are thought to be mediated by the inhibition of GADD34, a phosphatase subunit that promotes the production of proinflammatory cytokines and IFN-β. Perego et al. found that guanabenz inhibited the activation of TLR9, a receptor that induces type I IFN secretion from immune cells in response to DNA. TLR9 is implicated in autoimmune diseases in which self-DNA is erroneously recognized by the immune system, and guanabenz reduced symptom severity in a mouse model of lupus. However, guanabenz did not inhibit TLR9 by affecting GADD34 activity, but rather by altering cholesterol metabolism such that TLR9 did not reach endosomes where it is fully activated. The authors note that many lupus patients suffer from hypertension and that guanabenz and related compounds could, thus, have dual benefits for these patients. 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.