Modulation of the Itaconate Pathway Attenuates Murine Lupus

Abstract

Objective. Itaconic acid, a Krebs cycle-derived immunometabolite, is synthesized by myeloid cells in response to danger signals to control inflammasome activation, type I interferon (IFN) responses, and oxidative stress. As these pathways are dysregulated in systemic lupus erythematosus (SLE), we investigated the role of an itaconic acid derivative in the treatment of established murine lupus.Methods. Female (NZW × NZB)F 1 lupus-prone mice were administered 4-octyl itaconate (4-OI) or vehicle starting after clinical onset of disease (30 weeks of age) for 4 weeks (n = 10 mice /group). At 34 weeks of age (peak disease activity), animals were euthanized, organs and serum were collected, and clinical, metabolic, and immunologic parameters were evaluated.Results. Proteinuria, kidney immune complex deposition, renal scores of severity and inflammation, and anti-RNP autoantibodies were significantly reduced in the 4-OI treatment group compared to the vehicle group. Splenomegaly decreased in the 4-OI group compared to vehicle, with decreases in activation markers in innate and adaptive immune cells, increases in CD8+ T cell numbers, and inhibition of JAK1 activation. Gene expression analysis in splenocytes showed significant decreases in type I IFN and proinflammatory cytokine genes and increased Treg cell-associated markers in the 4-OI group compared to the vehicle group. In human control and lupus myeloid cells, 4-OI in vitro treatment decreased proinflammatory responses and B cell responses.Conclusions. These results support targeting immunometabolism as a potentially viable approach in autoimmune disease treatment, with 4-OI displaying beneficial roles attenuating immune dysregulation and organ damage in lupus.

The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers in SLE

“…6f ). These results support that endogenous itaconate modulates mitochondrial respiration in myeloid cells, as proposed for exogenous itaconate ( 20 ).…”

“…Similar to Acod1 -/models, esterified derivatives of itaconate, 4-octyl itaconate (4-OI) and dimethyl itaconate (DI), are commonly used to mimic ACOD1/Itaconate biological effects in vitro and in vivo (16). Indeed, 4-OI has beneficial effects in numerous in vivo animal models (17)(18)(19), including our recent findings that this compound attenuates immune dysregulation and organ damage in a mouse model of spontaneous lupus (20). In human studies, treatment of lupus PBMCs with 4-OI decreases the production of proinflammatory cytokines (21), while serum itaconate levels are decreased in SLE (22).…”

Itaconate: A Potent Macrophage Immunomodulator

“…In addition, the JAK/STAT signaling pathway is important in systemic lupus erythematosus [ 91 ]. A recent study found that 4-OI inhibited JAK1 activation and played beneficial roles in reducing immune dysregulation and organ damage in murine lupus [ 92 ]. In conclusion, the mechanism of itaconate in macrophage polarization is still complex, and further profound studies are needed to better understand the immunomodulatory role of itaconate in macrophages.…”

Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases

“…Itaconate, a TCA cycle mitochondrial-derived metabolite produced in response to inflammation, blunts oxidative stress, proinflammatory, and type I IFN-generating responses [ 56 ]. Lupus mice treated with an itaconate derivative showed significant attenuation of disease progression [ 57 ]. Furthermore, repairing the activity of oxyguanine glycosylase 1 (OGG1), an enzyme involved in excising damaged oxidized nucleic acids, attenuated skin lesions and immune dysregulation in pristane-induced murine lupus [ 58 ].…”