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

Abstract

What is already known on this topicAconitate Decarboxylase 1 (ACOD1) is an enzyme involved in the synthesis of itaconate, a metabolite generated during the Krebs cycle.Itaconate has been identified as an immunomodulatory moleculeACOD1/Itaconate has been studied in the context of various inflammatory and autoimmune diseases, including sepsis, inflammatory bowel disease and rheumatoid arthritis. In these conditions, dysregulation of itaconate metabolism has been associated with altered immune responses and disease progression.What this study adds1.Upon stimulation with lupus-relevant stimuli, ACOD1 expression is induced in myeloid cells.2.IN an induced mouse model of lupus, ACOD1 knockout (Acod1-/-) mice exhibit exacerbated lupus-like symptoms, implicating dysregulation of this pathway in the induction and severity of autoimmunity features.3.Itaconate serum levels are decreased in SLE patients, compared to healthy individuals. This decrease is associated with specific perturbed cardiometabolic parameters and subclinical atherosclerosis, indicating that modulating dysregulation of the itaconate pathway could have therapeutic benefits in this disease.How this study might affect research, practice or policyGiven its immunomodulatory effects, ACOD1/itaconate and its derivatives may have potential therapeutic benefit for the treatment of autoimmune diseases. They may also serve as putative biomarkers of cardiovascular risk in this disease.ObjectiveThe Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE.MethodsWe characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/-mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity.ResultsACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. Consistent with these results,Acod1-/-BMDM exposed to IMQ showed higher proinflammatory features in vitro. Itaconate levels were decreased in SLE serum compared to healthy control sera, in association with specific perturbed cardiometabolic parameters and subclinical vascular disease.ConclusionThese findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in SLE, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.