Gender differences in the relationship between the systemic immune-inflammation index and all-cause and cardiovascular mortality among adults with hypertension: evidence from NHANES 1999-2018.

Background: There are gender differences in hypertension and the effect of gender on the relationship between systemic immune-inflammation index (SII) and mortality in hypertensive patients is unclear. Methods: Hypertensive patients (n=7444) from ten cycles of the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018 were enrolled in this study. The maximally selected rank statistics method was employed to identify the optimal cut-off value for the SII. Survey-weighted Cox regression analysis was utilized to explore the links between SII and all-cause and cardiovascular mortality. Kaplan-Meier method and time-dependent receiver operating characteristic curve analysis was conducted to assess the predictive accuracy of SII for mortality. Results: Whether SII was considered as a numerical variable or as a binary variable (higher- and lower-SII groups), higher SII levels were associated with a higher risk of all-cause and cardiovascular mortality in female hypertensive patients (all P < 0.001), but no such association was observed in the males. The area under the curve of the SII was 0.602, 0.595, and 0.569 for 3-, 5-, and 10-year all-cause mortality, respectively, in females, but was 0.572, 0.548, and 0.554 in males. High SII levels interacted with the poverty income ratio and physical activity to affect mortality in the male population (P for interaction < 0.05), and there was an interaction between race and SII in the female cardiovascular mortality rate (P for interaction < 0.05). Conclusion: Higher levels of SII may be closely related to the high risk of all-cause and cardiovascular mortality in hypertensive patients, and the results showed that this relationship is more significant and stable in the female group. High SII interacts with PIR, physical activity, and race to affect the mortality rate in different gender populations.

Systemic inflammation markers independently associated with increased mortality in individuals with hyperuricemia: Results from the NHANES prospective cohort study.

BACKGROUND: Hyperuricemia is associated with increased systemic inflammation. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) are novel systemic inflammation markers and prognostic markers. However, no studies have evaluated the association between the SII/SIRI and mortality risk in individuals with hyperuricemia. This study aimed to investigate the predictive value of the SII and SIRI for all-cause and cardiovascular mortality in a large cohort of hyperuricemia patients. METHODS: We conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2020. Hyperuricemia was defined as serum uric acid (SUA) levels of ≥7 mg/dL in men and ≥6 mg/dL in women. The SII and SIRI were calculated based on complete blood count parameters. Associations with all-cause and cardiovascular mortality were analyzed using Cox proportional hazards models. Nonlinearity and effect modification were assessed using restricted cubic splines (RCS) and interaction analysis. RESULTS: Among the 6181 participants with hyperuricemia aged 20 years and older, over a total 181 months of follow-up, there were 936 all-cause deaths, of which 195 were cardiovascular mortality. In the fully adjusted models, the hazard ratios (HRs) were 1.73 (95% CI 1.42-2.13) for the SII and 2.18 (95% CI 1.82-2.62) for the SIRI with all-cause mortality. The adjusted HRs were 2.08 (95% CI 1.37-3.14) for the SII and 2.32 (95% CI 1.56-3.45) for the SIRI with cardiovascular mortality. Spline models identified nonlinear U-shaped (SII) and J-shaped (SIRI) relationships of inflammation markers with mortality. CONCLUSIONS: Elevated SII and SIRI are independent predictors of mortality in hyperuricemia patients. These inflammatory biomarkers may improve risk stratification in this high-risk population. Further research should evaluate utility in guiding preventive interventions.

Role of complement factor D in cardiovascular and metabolic diseases.

In the genesis and progression of cardiovascular and metabolic diseases (CVMDs), adipose tissue plays a pivotal and dual role. Complement factor D (CFD, also known as adipsin), which is mainly produced by adipocytes, is the rate-limiting enzyme of the alternative pathway. Abnormalities in CFD generation or function lead to aberrant immune responses and energy metabolism. A large number of studies have revealed that CFD is associated with CVMDs. Herein, we will review the current studies on the function and mechanism of CFD in CVMDs such as hypertension, coronary heart disease, ischemia/reperfusion injury, heart failure, arrhythmia, aortic aneurysm, obesity, insulin resistance, and diabetic cardiomyopathy.

Cardiovascular disease risk in systemic lupus erythematous: Certainties and controversies.

Patients with systemic lupus erythematosus (SLE) experience greater cardiovascular morbidity and mortality compared to the general population. It is known that endothelial dysfunction, an early indicator of atherosclerosis development, can arise even without the presence of conventional cardiovascular risk factors. In fact, the risk factors contributing to cardiovascular disease can be classified into traditional risk factors and those uniquely associated with SLE such as disease activity, autoantibodies, etc.Furthermore, the pathogenesis of cardiovascular disease in SLE is linked to the activation of both the innate and adaptive immune systems. Given these findings, it is essential for clinicians to acknowledge the heightened CVD risk in SLE patients, perform comprehensive screenings for cardiovascular risk factors, and implement aggressive treatment strategies for those who exhibit signs of clinical CVD. The aim of this review is to summarize the findings on cardiovascular disease in SLE and to examine potential screening and therapeutic strategies for clinical practice.

Current understanding and management of cardiovascular involvement in rheumatic immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are a spectrum of disorders of overlapping immunopathogenesis, with a prevalence of up to 10% in Western populations and increasing incidence in developing countries. Although targeted treatments have revolutionized the management of rheumatic IMIDs, cardiovascular involvement confers an increased risk of mortality and remains clinically under-recognized. Cardiovascular pathology is diverse across rheumatic IMIDs, ranging from premature atherosclerotic cardiovascular disease (ASCVD) to inflammatory cardiomyopathy, which comprises myocardial microvascular dysfunction, vasculitis, myocarditis and pericarditis, and heart failure. Epidemiological and clinical data imply that rheumatic IMIDs and associated cardiovascular disease share common inflammatory mechanisms. This concept is strengthened by emergent trials that indicate improved cardiovascular outcomes with immune modulators in the general population with ASCVD. However, not all disease-modifying therapies that reduce inflammation in IMIDs such as rheumatoid arthritis demonstrate equally beneficial cardiovascular effects, and the evidence base for treatment of inflammatory cardiomyopathy in patients with rheumatic IMIDs is lacking. Specific diagnostic protocols for the early detection and monitoring of cardiovascular involvement in patients with IMIDs are emerging but are in need of ongoing development. This Review summarizes current concepts on the potentially targetable inflammatory mechanisms of cardiovascular pathology in rheumatic IMIDs and discusses how these concepts can be considered for the diagnosis and management of cardiovascular involvement across rheumatic IMIDs, with an emphasis on the potential of cardiovascular imaging for risk stratification, early detection and prognostication.

Exploring the roles of SPARC as a proinflammatory factor and its potential as a novel therapeutic target against cardiovascular disease.

Cardiovascular disease (CVD) is a leading cause of death worldwide, and the number of patients with CVD continues to increase despite extensive research and developments in this field. Chronic inflammation is a pivotal pathological component of CVD, and unveiling new proinflammatory factors will help devise novel preventive and therapeutic strategies. The extracellular matrix (ECM) not only provides structural support between cells but also contributes to cellular functions. Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein that is particularly induced during development and tissue remodeling. A proinflammatory role for SPARC has been demonstrated in various animal models, such as in the lipopolysaccharide-induced footpad model and dextran sodium sulfate-induced colitis model. Recent clinical studies reported a positive correlation between elevated plasma SPARC levels and hypertension, obesity, and the inflammatory marker high-sensitive C-reactive protein. In addition, SPARC gene deletion attenuates the cardiac injury induced by aging, myocardial infarction, and pressure load, suggesting that SPARC has deleterious effects on CVD. This review summarizes the regulatory and proinflammatory mechanisms of SPARC on CVD, chronic kidney disease (CKD), and cerebrovascular disease and discusses the rationale behind measuring SPARC as a biomarker of CVD and the effects of inhibition of SPARC in the prevention and treatment of CVD.

Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases.

PURPOSE OF THE REVIEW: Macrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease. RECENT FINDINGS: Dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function. Targeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.

Neutrophil-lymphocyte ratio and systemic immune-inflammation index as predictors of cardiovascular risk and mortality in prediabetes and diabetes: a population-based study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) are emerging inflammatory markers related to cardiovascular outcomes. This study investigated their relationships with cardiovascular disease (CVD) and mortality among individuals with prediabetes or diabetes and assessed their predictive roles. METHODS: A cohort of 6871 individuals with diabetes or prediabetes from the NHANES (2001-2018) was included. Weighted multivariate logistic regression models assessed NLR and SII associations with CVD risk, while survey-weighted Cox proportional hazards models evaluated their links to mortality. The predictive accuracy of the biomarkers for mortality was quantified by receiver-operating characteristic (ROC) curve analysis. RESULTS: Individuals in the higher NLR and SII groups exhibited a high incidence of CVD. A total of 1146 deaths occurred throughout an average follow-up duration of 191 months, of which 382 were caused by CVD. Participants with higher NLR markedly increased the risk of all-cause (HR = 1.82) and cardiovascular mortality (HR = 2.07). A similar result was observed in the higher SII group. RCS analysis identified a linear correlation between NLR and CVD risk and mortality (p > 0.05), while SII showed a nonlinear correlation (p < 0.05). ROC results demonstrated that NLR exhibited a higher predictive ability in mortality than SII. CONCLUSIONS: Elevated levels of NLR and SII correlated with an increased risk of CVD and both all-cause and cardiovascular mortality in individuals with diabetes or prediabetes. The NLR appears to be particularly valuable for assessing risk and predicting outcomes in these patients.

Phenotypes and functions of "aged" neutrophils in cardiovascular diseases.

Neutrophils are important effector cells of innate immunity and undergo several phenotypic changes after release from the bone marrow. Neutrophils with a late life cycle phenotype are often referred to as "aged" neutrophils. These neutrophils undergo functional changes that accompany stimuli of inflammation, tissue senescence and injury, inducing their maturation and senescence in the circulation and locally in damaged tissues, forming a unique late-life neutrophil phenotype. "Aged" neutrophils, although attenuated in antibacterial capacity, are more active in aging and age-related diseases, exhibit high levels of mitochondrial ROS and mitochondrial DNA leakage, promote senescence of neighboring cells, and exacerbate cardiac and vascular tissue damage, including vascular inflammation, myocardial infarction, atherosclerosis, stroke, abdominal aortic aneurysm, and SARS-CoV-2 myocarditis. In this review, we outline the phenotypic changes of "aged" neutrophils characterized by CXCR4high/CD62Llow, investigate the mechanisms driving neutrophil aging and functional transformation, and analyze the damage caused by "aged" neutrophils to various types of heart and blood vessels. Tissue injury and senescence promote neutrophil infiltration and induce neutrophil aging both in the circulation and locally in damaged tissues, resulting in an "aged" neutrophil phenotype characterized by CXCR4high/CD62Llow. We also discuss the effects of certain agents, such as neutralizing mitochondrial ROS, scavenging IsoLGs, blocking VDAC oligomers and mPTP channel activity, activating Nrf2 activity, and inhibiting neutrophil PAD4 activity, to inhibit neutrophil NET formation and ameliorate age-associated cardiovascular disease, providing a new perspective for anti-aging therapy in cardiovascular disease.

Monocyte Single-Cell Multimodal Profiling in Cardiovascular Disease Risk States.

BACKGROUND: Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. They have been identified historically by the cell surface expression of CD14 and CD16. However, recent single-cell studies have revealed that they are much more heterogeneous than previously realized. METHODS: We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing to describe the comprehensive transcriptional and phenotypic landscape of 437 126 monocytes. RESULTS: This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi (major histocompatibility complex class II), monocyte-platelet aggregates, as well as nonclassical, and several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+ MHCIIhi, CD42b+ monocyte-platelet aggregates, CD16+CD99- nonclassical monocytes, and CD99+ classical monocytes. Each subpopulation exhibited unique characteristics, developmental trajectories, transcriptional regulation, and tissue distribution. In addition, alterations associated with cardiovascular disease risk factors, including race, smoking, and hyperlipidemia were identified. Moreover, the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. CONCLUSIONS: This integrative and cross-species comparative analysis provides a new perspective on the comparison of alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in cardiovascular disease and the potential for monocyte subpopulation targeted therapies.

Association between systemic immune-inflammation index and cardiovascular-kidney-metabolic syndrome.

This study aims to explore the relationship between the Systemic Immune-Inflammation Index (SII) and Cardiovascular-Kidney-Metabolic (CKM) Syndrome and its components. Data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018 were analyzed. CKM Syndrome is defined as the coexistence of Cardiometabolic Syndrome (CMS) and Chronic Kidney Disease (CKD). The SII is calculated using the formula: SII = (Platelet count × Neutrophil count)/Lymphocyte count. Weighted logistic regression models were used to examine the associations between SII and CKM, as well as its specific components. Restricted cubic splines explored non-linear relationships, and piecewise linear regression models assessed threshold effects. A consistent positive correlation was observed between elevated SII levels and the likelihood of CKM and its related diseases. In the fully adjusted Model 3, an increase of 1000 units in SII was associated with a 1.48-fold increase in the odds of CKM (95% CI 1.20-1.81, p < 0.001). Quartile analysis revealed a dose-response relationship, with the highest quartile of SII (Q4) showing the strongest association with CKM and its components. Nonlinear analyses revealed inflection points for waist circumference, triglycerides, low HDL-C, and cardiometabolic syndrome at specific SII levels, indicating a change in the direction or strength of associations beyond these points. Conversely, a linear relationship was observed between SII and chronic kidney disease. The SII is positively correlated with the risk of CKM Syndrome and its individual components, with evidence of non-linear relationships and threshold effects for some components.

Synergy Between NK Cells and Monocytes in Potentiating Cardiovascular Disease Risk in Severe COVID-19.

BACKGROUND: Evidence suggests that COVID-19 predisposes to cardiovascular diseases (CVDs). While monocytes/macrophages play a central role in the immunopathogenesis of atherosclerosis, less is known about their immunopathogenic mechanisms that lead to CVDs during COVID-19. Natural killer (NK) cells, which play an intermediary role during pathologies like atherosclerosis, are dysregulated during COVID-19. Here, we sought to investigate altered immune cells and their associations with CVD risk during severe COVID-19. METHODS: We measured plasma biomarkers of CVDs and determined phenotypes of circulating immune subsets using spectral flow cytometry. We compared these between patients with severe COVID-19 (severe, n=31), those who recovered from severe COVID-19 (recovered, n=29), and SARS-CoV-2-uninfected controls (controls, n=17). In vivo observations were supported using in vitro assays to highlight possible mechanistic links between dysregulated immune subsets and biomarkers during and after COVID-19. We performed multidimensional analyses of published single-cell transcriptome data of monocytes and NK cells during severe COVID-19 to substantiate in vivo findings. RESULTS: During severe COVID-19, we observed alterations in cardiometabolic biomarkers including oxidized-low-density lipoprotein, which showed decreased levels in severe and recovered groups. Severe patients exhibited dysregulated monocyte subsets, including increased frequencies of proinflammatory intermediate monocytes (also observed in the recovered) and decreased nonclassical monocytes. All identified NK-cell subsets in the severe COVID-19 group displayed increased expression of activation and tissue-resident markers, such as CD69 (cluster of differentiation 69). We observed significant correlations between altered immune subsets and plasma oxidized-low-density lipoprotein levels. In vitro assays revealed increased uptake of oxidized-low-density lipoprotein into monocyte-derived macrophages in the presence of NK cells activated by plasma of patients with severe COVID-19. Transcriptome analyses confirmed enriched proinflammatory responses and lipid dysregulation associated with epigenetic modifications in monocytes and NK cells during severe COVID-19. CONCLUSIONS: Our study provides new insights into the involvement of monocytes and NK cells in the increased CVD risk observed during and after COVID-19.

Overview of multifunctional Tregs in cardiovascular disease: From insights into cellular functions to clinical implications.

Regulatory T cells (Tregs) are crucial in regulating T-cell-mediated immune responses. Numerous studies have shown that dysfunction or decreased numbers of Tregs may be involved in inflammatory cardiovascular diseases (CVDs) such as atherosclerosis, hypertension, myocardial infarction, myocarditis, cardiomyopathy, valvular heart diseases, heart failure, and abdominal aortic aneurysm. Tregs can help to ameliorate CVDs by suppressing excessive inflammation through various mechanisms, including inhibition of T cells and B cells, inhibition of macrophage-induced inflammation, inhibition of dendritic cells and foam cell formation, and induction of anti-inflammatory macrophages. Enhancing or restoring the immunosuppressive activity of Tregs may thus serve as a fundamental immunotherapy to treat hypertension and CVDs. However, the precise molecular mechanisms underlying the Tregs-induced protection against hypertension and CVDs remain to be investigated. This review focuses on recent advances in our understanding of Tregs subsets and function in CVDs. In addition, we discuss promising strategies for using Tregs through various pharmacological approaches to treat hypertension and CVDs.

Neuroimmune crosstalk : How mental stress fuels vascular inflammation.

Cardiovascular diseases are the leading cause of death worldwide. Pathophysiologically, metabolic and inflammatory processes contribute substantially to the development and progression of cardiovascular diseases. Over the past decade, the role of disease-propagating inflammatory processes has been strengthened and reframed, leading to trials testing anti-inflammatory drugs for the treatment of atherosclerosis and its complications. Despite these achievements, further research in both pre-clinical and clinical studies is warranted to explore new targets, to better identify responders, and to refine therapy strategies to combat inflammation in human disease. Environmental disturbances, so-called lifestyle-associated cardiovascular risk factors, greatly alter the immune system in general and leukocytes in particular, thus affecting the progression of atherosclerosis. Epidemiological studies have shown that exposure to mental stress can be closely linked to the occurrence of cardiovascular disease. Here, we describe how acute and chronic mental stress alter the immune system via neuroimmune interactions, thereby modifying vascular inflammation. In addition, we identify gaps that still need to be addressed in the future.

Combining Bibliometric Analysis to Uncover the Detrimental and Protective Roles of Various Dendritic Cell Types in Cardiovascular Arterial Diseases.

Immune cell dysregulation is increasingly recognized as a pivotal pathological factor in cardiovascular disease. Over the past decade, a surge of research has focused on the role of immune cells such as dendritic cells (DCs), T cells, macrophages, and neutrophils in cardiovascular diseases, findings that are frequently featured in leading cardiology journals. This review provides a comprehensive synthesis of the roles that DCs play in common and potentially fatal arterial diseases, including hypertension, coronary artery atherosclerosis, acute coronary syndrome, pulmonary arterial hypertension, aortic aneurysm, aortic dissection, and vasculitis. Combining with bibliometric analysis, this review delves into the critical mechanisms by which DCs contribute to these diseases and reveals the shared mechanisms across diverse diseases. This review also offers new advances in clinical treatment strategies involving DCs.

Nonlinear associations of systemic immune-inflammation index with all-cause and cardiovascular mortality in US adults with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease. However, the relationship between the systemic immune-inflammation index (SII) and the prognosis of RA patients remains unclear. This study aimed to investigate the association between inflammatory biomarker SII and all-cause and cardiovascular mortality in RA patients. A retrospective analysis was conducted using data from the National Health and Nutrition Examination Survey database spanning from 1999 to March 2020. We assessed the association between the SII and all-cause as well as cardiovascular mortality in RA patients employing multivariable Cox proportional hazards regression analysis and restricted cubic spline plots. Receiver operating characteristic curves were employed to evaluate the prognostic capacity of SII in predicting outcomes in both the RA patients and the general population, alongside its predictive performance compared to other markers. This study comprised 2247 RA patients and a control cohort of 29,177 individuals from the general population. Over a 20-year follow-up period, 738 all-cause deaths and 215 deaths attributable to cardiovascular disease were documented in RA patients. We observed a nonlinear positive correlation between the SII and both all-cause and cardiovascular mortality in RA patients. Of significance, at an SII level of 529.7, the hazard ratio reached 1, signifying a transition from low to high mortality risk. Moreover, subgroup analysis did not reveal any potential interactions. Our study findings indicate a nonlinear positive correlation between the inflammatory biomarker SII and both all-cause and cardiovascular mortality in patients with RA.

PANoptosis: a novel target for cardiovascular diseases.

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

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

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.