FIG. 7.

Proposed model of the mechanisms by which metformin reduces lupus pathogenesis. In the oxidative state presented by immune cells in SLE, enhanced mROS synthesis in neutrophils leads to increased NETosis (1). Oxidized mtDNA produced by NETosis (2) induces pDCs to secrete type I IFN (3). Increased mROS production enhances TCR-induced T cell activation as well as T cell death (4). Metformin has been reported to inhibit the functions of neutrophils, CD4⁺ T cells, pDCs and B cells in either SLE patients or mouse models of the disease. Only neutrophils and CD4⁺ T cells present a direct involvement of mROS in their pathogenic phenotypes in SLE. The functions of pDCs and B cells may be inhibited by metformin through mROS-independent pathways, or as a consequence of neutrophils and T cell inhibition, respectively. Alternatively, mROS may contribute to pDC and B cell dysfunction in SLE, and metformin may function through a common mechanism in multiple pathogenic cell types in SLE. TCR, T cell receptor; mtDNA, mitochondrial DNA. Color images are available online.