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

Autor:	Patiño-Martinez E; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA., Nakabo S; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA., Jiang K; Biodata Mining and Discovery Section, NIAMS/NIH., Carmona-Rivera C; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA., Tsai WL; Translational Immunology Section, NIAMS/NIH., Claybaugh D; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA., Yu ZX; National Heart, Lung, and Blood Institute (NHLBI), NIH., Romero A; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA., Bohrnsen E; Protein & Chemistry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Hamilton, MT, USA., Schwarz B; Protein & Chemistry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Hamilton, MT, USA., Solís-Barbosa MA; Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del I.P.N, 07360 Mexico City, Mexico., Blanco LP; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA., Naqi M; Lupus Clinical Trials Unit, NIAMS/NIH., Temesgen-Oyelakim Y; Lupus Clinical Trials Unit, NIAMS/NIH., Davis M; Lupus Clinical Trials Unit, NIAMS/NIH., Manna Z; Lupus Clinical Trials Unit, NIAMS/NIH., Mehta N; National Heart, Lung, and Blood Institute (NHLBI), NIH., Naz F; Office of Science and Technology, NIAMS/NIH., Brooks S; Office of Science and Technology, NIAMS/NIH., dell'Orso S; Office of Science and Technology, NIAMS/NIH., Hasni S; Lupus Clinical Trials Unit, NIAMS/NIH., Kaplan MJ; Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Feb 22. Date of Electronic Publication: 2024 Feb 22.
DOI:	10.1101/2024.02.20.24303097
Abstrakt:	Objective: The 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. Methods: We 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. Results: ACOD1 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. Conclusion: These 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. Competing Interests: There are no conflicts of interest.
Databáze:	MEDLINE
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