Research ArticleImmunology

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

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Sci. Signal.  23 Jan 2018:
Vol. 11, Issue 514, eaam8104
DOI: 10.1126/scisignal.aam8104

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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.