The Aconitate Decarboxylase 1/Itaconate Pathway Modulates Immune Dysregulation and Associates with Cardiovascular Disease Markers and Disease Activity in Systemic Lupus Erythematosus-Reference-Cited by-同舟云学术

The Aconitate Decarboxylase 1/Itaconate Pathway Modulates Immune Dysregulation and Associates with Cardiovascular Disease Markers and Disease Activity in Systemic Lupus Erythematosus

Published:2024-07-01 Issue:4 Volume:213 Page:419-434
ISSN:0022-1767
Container-title:The Journal of Immunology
language:en
Short-container-title:

Author:

Patiño-Martinez Eduardo¹,Nakabo Shuichiro¹^ORCID,Jiang Kan²^ORCID,Carmona-Rivera Carmelo¹^ORCID,Tsai Wanxia Li³,Claybaugh Dillon¹^ORCID,Yu Zu-Xi⁴,Romero Aracely¹^ORCID,Bohrnsen Eric⁵,Schwarz Benjamin⁵^ORCID,Solís-Barbosa Miguel A.⁶,Blanco Luz P.¹^ORCID,Naqi Mohammad⁷,Temesgen-Oyelakin Yenealem⁷,Davis Michael⁷,Manna Zerai⁷^ORCID,Gupta Sarthak⁷,Mehta Nehal⁸,Naz Faiza⁹^ORCID,dell’Orso Stefania⁹,Hasni Sarfaraz⁷^ORCID,Kaplan Mariana J.¹^ORCID

Affiliation:

1. *Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

2. †Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

3. ‡Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

4. §National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

5. ¶Protein & Chemistry Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT

6. ǁDepartamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico

7. #Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

8. **National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

9. ††Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

Abstract

Abstract The Krebs cycle enzyme aconitate decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Previously, we reported that administration of 4-octyl itaconate to lupus-prone mice abrogated immune dysregulation and clinical features. In this study, we explore the role of the endogenous ACOD1/itaconate pathway in the development of TLR7-induced lupus (imiquimod [IMQ] model). We found that, in vitro, ACOD1 was induced in mouse bone marrow–derived macrophages and human monocyte-derived macrophages following TLR7 stimulation. This induction was partially dependent on type I IFN receptor signaling and on specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1−/−) displayed disruptions of the splenic architecture, increased serum levels of anti-dsDNA and proinflammatory cytokines, and enhanced kidney immune complex deposition and proteinuria, when compared with the IMQ-treated wild-type mice. Consistent with these results, Acod1−/− bone marrow–derived macrophages treated in vitro with IMQ showed higher proinflammatory features. Furthermore, itaconate serum levels in systemic lupus erythematosus patients were decreased compared with healthy individuals, in association with disease activity and specific perturbed cardiometabolic parameters. These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in systemic lupus erythematosus, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

Funder

HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases

Publisher

The American Association of Immunologists

Link

https://journals.aai.org/jimmunol/article-pdf/213/4/419/1659955/ji2400241.pdf

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