Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3

Abstract

Circulating autoantibodies and immune complex deposition are pathological hallmarks of systemic lupus erythematosus (SLE). B cell differentiation into plasma cells (PCs) and some T cell subsets that function as B cell helpers can be therapeutic targets of SLE. Mechanistic target of rapamycin (mTOR) signaling is implicated in the formation of B cells and germinal centers (GCs). We assessed the effect of metformin, which inhibits mTOR, on the development of autoimmunity using Roquinsan/san mice. Oral administration of metformin inhibited the formation of splenic follicles and inflammation in kidney and liver tissues. It also decreased serum levels of anti-dsDNA Abs without affecting serum glucose levels. Moreover, metformin inhibited CD21highCD23low marginal zone B cells, B220+GL7+ GC B cells, B220−CD138+ PCs, and GC formation. A significant reduction in ICOS+ follicular helper T cells was found in the spleens of the metformin-treated group compared with the vehicle-treated group. In addition, metformin inhibited Th17 cells and induced regulatory T cells. These alterations in B and T cell subsets by metformin were associated with enhanced AMPK expression and inhibition of mTOR–STAT3 signaling. Furthermore, metformin induced p53 and NF erythroid-2–related factor-2 activity in splenic CD4+ T cells. Taken together, metformin-induced alterations in AMPK–mTOR–STAT3 signaling may have therapeutic value in SLE by inhibiting B cell differentiation into PCs and GCs.

Metabolic abnormalities and oxidative stress in lupus

“…Oral administration of metformin in Roquin san/san mice, not only normalized T cell responses [i.e. reduced the frequencies of Tfh and T helper 17 (Th17) cells, while enhancing Treg numbers], but also suppressed the development of autoantibody-producing plasma cells and germinal center formation via the AMPK-mTOR signaling pathway [36]. These studies indicate that elucidating key metabolic programs involved in the pathogenesis of SLE may facilitate the modulation of multiple immune cell subsets with a single target and/or therapy.…”

The effects of metformin on gut microbiota and the immune system as research frontiers

“…Experimental evidence [44] suggests that metformin can influence CD4 T cell metabolism and reduce autoimmunity in a manner that improves experimental systemic lupus. An additional study [45] suggests that the mechanism involved in reduction of autoimmunity requires AMPK activation, which is achieved as a consequence of inhibition of oxidative phosphorylation in B cells. Metformin also reduces inflammation associated with pulmonary tuberculosis [49], but further work is needed to clarify the relative importance of effects on the host vs the Mycobacterium itself.…”

“…Although no detailed clinical studies examining influences of metformin on more subtle aspects of immune function have been carried out, laboratory studies [34][35][36][37][38][39][40][41][42][43][44][45] have provided considerable evidence for a variety of immunomodulatory effects.…”

“…While the notion that metformin may influence immune function as a consequence of altering energy metabolism in the many cell lineages that comprise the immune system is straightforward, it is unclear what subpopulations of immune cells are most affected by the drug, and therefore what the net effect on immune function would be in different clinical contexts. Recent results in tumour immunology provide examples of enhanced immune function as a consequence of metformin exposure [36][37][38], while studies in other contexts, including tuberculosis and multiple sclerosis, suggest anti-inflammatory actions [40][41][42][43][44][45].…”

Immune cell metabolism in autoimmunity

“…In the Roquin mouse model of lupus, activation of AMPK and inhibition of mTOR limited B cell differentiation into GC B and plasma cells, which was associated with a reduced disease activity [27]. In SLE patients, high mTOR activation in CD19 + B cells correlates with plasmablast numbers and disease activity [28] (Fig.…”