Metformin inhibits the type 1 IFN response in human CD4+ T cells

Anton A. Titov, Henry V. Baker, Todd M. Brusko, Eric S. Sobel, Laurence Morel

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

In systemic lupus erythematosus, defective clearance of apoptotic debris and activation of innate cells result in a chronically activated type 1 IFN response, which can be measured in PBMCs of most patients. Metformin, a widely used prescription drug for Type 2 diabetes, has a therapeutic effect in several mouse models of lupus through mechanisms involving inhibition of oxidative phosphorylation and a decrease in CD4+ T cell activation. In this study, we report that in CD4+ T cells from human healthy controls and human systemic lupus erythematosus patients, metformin inhibits the transcription of IFN-stimulated genes (ISGs) after IFN-a treatment. Accordingly, metformin inhibited the phosphorylation of pSTAT1 (Y701) and its binding to IFN-stimulated response elements that control ISG expression. These effects were independent of AMPK activation or mTORC1 inhibition but were replicated using inhibitors of the electron transport chain respiratory complexes I, III, and IV. This indicates that mitochondrial respiration is required for ISG expression in CD4+ T cells and provides a novel mechanism by which metformin may exert a therapeutic effect in autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)338-348
Number of pages11
JournalJournal of Immunology
Volume203
Issue number2
DOIs
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Metformin inhibits the type 1 IFN response in human CD4+ T cells'. Together they form a unique fingerprint.

Cite this