This study utilized Mendelian randomization (MR) to investigate the impact of inflammatory proteins on knee osteoarthritis (KOA), measured using the ratio of protein levels (rQTLs). The primary objective was to identify potential intervention targets to mitigate KOA progression. Data from 2821 rQTLs, 91 inflammatory proteins, and KOA-related genetic variations were obtained through genome-wide association studies (GWAS). Bidirectional MR identified rQTLs with unidirectional causal relationships with KOA. Further analyses included false discovery rate (FDR) correction, colocalization, and mediation analysis. Two inflammatory proteins were found to be associated with KOA: T-cell surface glycoprotein CD5 [OR (95% CI) = 0.867 (0.760-0.990), PIVW = 0.035] and C-X-C motif chemokine 9 [OR (95% CI) = 1.150 (1.001-1.320), PIVW = 0.048]. Variations in their levels influenced rQTLs, producing differential effects on KOA. Specifically, rQTL-ANGPTL3/TFPI (human recombinant angiopoietin-like protein 3/Tissue factor pathway inhibitor) was identified as a mediator in the effect of T-cell surface glycoprotein CD5 levels on KOA. T-cell surface glycoprotein CD5 levels were negatively correlated with rQTL-ANGPTL3/TFPI (β1 = -0.084), while rQTL-ANGPTL3/TFPI was positively correlated with KOA (β2 = 0.159). These findings align with the total effect, where T-cell surface glycoprotein CD5 levels were negatively associated with KOA (β = -0.143). Thus, rQTL-ANGPTL3/TFPI may serve as a reliable mediator in the pathway through which T-cell surface glycoprotein CD5 levels affect KOA. This mediator may not only represent a potential therapeutic target but also serve as a biomarker for assessing KOA treatment efficacy, offering a novel direction for KOA diagnosis and management.

Myocardial infarction (MI), which is characterized by high morbidity and mortality, is a serious threat to human life and health, and timely reperfusion therapy to save ischemic myocardium is currently the most effective intervention. Although reperfusion therapy effectively restores coronary blood flow and maximally limits the infarct size, it triggers additional cell death and tissue damage, which is known as myocardial ischemia/reperfusion injury (MIRI). Multiple immune cells are present in the reperfusion area, executing specific functions and engaging in crosstalk during diverse stages, constituting a complex immune microenvironment involved in tissue repair and regeneration after MIRI. Immunotherapy brings new hope for treating ischemic heart disease by modulating the immune microenvironment. In this paper, we explore the regulatory roles of various immune cells during MIRI and the close relationship between different cell deaths and the immune microenvironment. In addition, we present the current status of research on targeting the immune system to intervene in MIRI, with the expectation of providing a basis for achieving clinical translation.

Atherosclerosis, traditionally considered a lipid-related disease, is now understood as a chronic inflammatory condition with significant global health implications.

This review aims to delve into the complex interactions among immune cells, cytokines, and the inflammatory cascade in atherosclerosis, shedding light on how these elements influence both the initiation and progression of the disease.

This review draws on recent clinical research to elucidate the roles of key immune cells, macrophages, T cells, endothelial cells, and clonal hematopoiesis in atherosclerosis development. It focuses on how these cells and process contribute to disease initiation and progression, particularly through inflammation-driven processes that lead to plaque formation and stabilization. Macrophages ingest oxidized low-density lipoprotein (oxLDL), which partially converts to high-density lipoprotein (HDL) or accumulates as lipid droplets, forming foam cells crucial for plaque stability. Additionally, macrophages exhibit diverse phenotypes within plaques, with pro-inflammatory types predominating and others specializing in debris clearance at rupture sites. The involvement of CD4+ T and CD8+ T cells in these processes promotes inflammatory macrophage states, suppresses vascular smooth muscle cell proliferation, and enhances plaque instability.

The nuanced roles of macrophages, T cells, and the related immune cells within the atherosclerotic microenvironment are explored, revealing insights into the cellular and molecular pathways that fuel inflammation. This review also addresses recent advancements in imaging and biomarker technology that enhance our understanding of disease progression. Moreover, it points out the limitations of current treatment and highlights the potential of emerging anti-inflammatory strategies, including clinical trials for agents such as p38MAPK, tumor necrosis factor α (TNF-α), and IL-1β, their preliminary outcomes, and the promising effects of canakinumab, colchicine, and IL-6R antagonists.

This review explores cutting-edge anti-inflammatory interventions, their potential efficacy in preventing and alleviating atherosclerosis, and the role of nanotechnology in delivering drugs more effectively and safely.

Intraplaque hemorrhage plays a critical role in the life of advancing atherosclerotic plaques, not only by triggering an acute increase in lesion size but also by attracting macrophages to the site. Lysis of erythrocytes in these areas is thought to be caused by oxidative stress, which induces the release of free Hb (hemoglobin), which is quickly bound by haptoglobin to form Hb-haptoglobin complexes. Macrophages are the only cells in the body capable of scavenging these complexes through the CD (cluster of differentiation) 163 scavenger receptor, which mediates Hb-haptoglobin ingestion, driving their differentiation. Emerging data suggest that these Hb-stimulated macrophages play an essential role in responding to intraplaque hemorrhage through mediating iron metabolism and influencing other cell types, including endothelial and smooth muscle cells. This review focuses on the role of Hb-stimulated macrophages in promoting atherogenesis through their effects on (1) endothelial activation, neoangiogenesis, and vascular permeability; (2) endothelial-to-mesenchymal cell transition and subsequent apoptosis; and (3) the prevention of smooth muscle cell osteogenic transformation and calcification. These functions may also be relevant to other vascular diseases where erythrocyte accumulation drives the formation of Hb-stimulated macrophages, which is a fundamental response to hemorrhage no matter the clinical setting.

Perfluorinated compounds (PFCs) are a well-recognized environmental risk factor for atherosclerosis. However, corresponding atherogenic risk in susceptible populations consuming high-fat diets (HFDs) remains unclear. Here, we found that perfluorooctane sulfonic acid (PFOS), a canonical PFCs, elevated the atherogenic risk in mice fed with HFD, which was characterized by an increased number of pro-inflammatory phenotype macrophages. We also found that macrophages exhibited a metabolic reprogramming to glycolysis, which was attributed to increased intracellular Fe2+ level. Mechanistic investigation revealed that PFOS directly bound to the iron-storage site on the ferritin heavy chain, subsequently weakening the iron-storage function. Notably, PFCs with acidic substituents and short chains had a higher atherogenic risk, as evidenced in the crucial indicators and observed in a population with a high triglyceride level. These findings highlight the potential atherogenic risk posed by PFCs exposure in susceptible populations consuming HFD and provide a potential intervention target.

Trastuzumab (TRZ) is the standard treatment for human epidermal growth factor receptor 2 (HER-2) positive breast cancer, but its cardiotoxicity significantly impacts the prognosis and quality of survival of patients, and the underlying mechanism of TRZ-related cardiotoxicity remains incompletely understood. Macrophage subsets better reflect macrophage heterogeneity than the traditional macrophage M1/M2 type polarization classification. CD74, a receptor with strong binding affinity for macrophage migration inhibitory factor, plays an important role in macrophage activation. After successfully constructing a mouse TRZ cardiotoxicity model, flow cytometry indicated that CD74+ cardiac macrophages (CMφs) were significantly elevated in the TRZ group. Single-cell data were utilized to identify CD74+ CMφs, GO and KEGG analyses of the DEGs were conducted to further validate the CD74/STAT1 signaling pathway. Analyses using RT-PCR, immunofluorescence, and western blot revealed a marked increase in the expression of genes and proteins linked to this pathway in TRZ-treated group. Additionally, levels of inflammation-related factors and the expression of apoptotic proteins was elevated following TRZ treatment. CD74-knockdown RAW 264.7 macrophages cell line were constructed via Lentiviruses carrying CD74 (hU6-MCS-CBh-gcGFP-IRES-puromycin) transfection and co-cultured with HL-1 cardiomyocytes to establish an in vitro TRZ cardiotoxicity model. Western blot analysis of CD74/STAT1 signaling pathway protein levels demonstrated that CD74 knockdown rescued TRZ-induced cellular damage. These findings suggest that TRZ may promote inflammation and apoptosis in cardiomyocytes, leading to cardiotoxicity through the CD74+ CMφ subset, which regulates the CD74/STAT1 signaling pathway. CD74+ CMφs are anticipated to be a novel intervention target and therapeutic strategy for addressing TRZ-induced cardiotoxicity.

Oxidation of lipids, excessive cell death, and iron deposition are prominent features of human atherosclerotic plaques. While extensive research has established the detrimental roles of lipid oxidation and apoptosis in atherosclerosis development, the involvement of iron in atherogenesis is not yet fully understood. With the emergence of an iron-dependent form of cell death termed ferroptosis, new attention has been brought to the complex inter-play among iron, ferroptosis, and atherosclerosis. Mechanistically, ferroptosis is caused by the lethal accumulation of iron-mediated lipid peroxides. Emerging studies have underscored ferroptosis as a contributor to worsened atherosclerosis. Herein, we review the evidence that oxidative damage and iron overload in the context of atherosclerosis may promote ferroptosis within plaques. Furthermore, we summarize recent findings of lipid peroxidation, thereby potentially ferroptosis, in various plaque cell types-such as endothelial cells, macrophages, dendritic cells, T cells, and vascular smooth muscle cells-across different stages of atherosclerosis. Understanding how these processes influence atherosclerotic plaque progression may permit targeting stage-dependent ferroptosis in each cell population and could provide a rationale for developing cell type-specific intervention strategies to mitigate atherogenic ferroptosis effectively.

Atherosclerosis is a lipid disorder where modified lipids (especially oxidized LDL) induce macrophage foam cell formation in the aorta. Its pathogenesis involves a continuum of persistent inflammation accompanied by dysregulated anti-inflammatory responses. Changes in the immune cell status due to differences in the lesional microenvironment are crucial in terms of plaque development, its progression, and plaque rupture. Ly6Chi monocytes generated through both medullary and extramedullary cascades act as one of the major sources of plaque macrophages and thereby foam cells. Both monocytes and monocyte-derived macrophages also participate in pathological events in atherosclerosis-associated multiple organ systems through inter-organ communications. For years, macrophage phenotypes M1 and M2 have been shown to perpetuate inflammatory and resolution responses; nevertheless, such a dualistic classification is too simplistic and contains severe drawbacks. As the lesion microenvironment is enriched with multiple mediators that possess the ability to activate macrophages to diverse phenotypes, it is obvious that such cells should demonstrate substantial heterogeneity. Considerable research in this regard has indicated the presence of additional macrophage phenotypes that are exclusive to atherosclerotic plaques, namely Mox, M4, Mhem, and M(Hb) type. Furthermore, although the concept of macrophage clusters has come to the fore in recent years with the evolution of high-dimensional techniques, classifications based on such 'OMICS' approaches require extensive functional validation as well as metabolic phenotyping. Bearing this in mind, the current review provides an overview of the status of different macrophage populations and their role during atherosclerosis and also outlines possible therapeutic implications.

Macrophages are the most important immune cells affecting the formation of atherosclerotic plaque. Nevertheless, the mechanisms that promote formation of foamy macrophages during atherogenesis remain poorly understood. This study explored the effects of Farnesoid X receptor (FXR) and hepatic lipase (HL, encoded by LIPC) on atherogenesis, particularly in foamy macrophage formation. A luciferase reporter assay indicated that FXR could bind to the LIPC promoter and inhibit LIPC transcription. FXR agonist GW4064 decreased HL expression, foam cell formation, and increased the expression of FXR downstream genes and polarization to M2 in ox-LDL-induced THP-1 and U937 foam cells. In addition, GW4064 exerted anti-atherosclerotic effects in ApoE-/- mice, manifested as decreased serum cholesterol and triglyceride levels, and alleviated atherosclerotic plaque formation. Collectively, FXR exerted anti-atherosclerotic effects, possibly by negatively regulating HL expression in macrophages.

Atherosclerosis, a multifactorial progressive inflammatory disease, is the common pathology underlying cardiovascular and cerebrovascular diseases. The macrophage plasticity is involved in the pathogenesis of atherosclerosis. With the advance of metabolomics and epigenetics, metabolites/metabolic and epigenetic modification such as DNA methylation, histone modification and noncoding RNA, play a crucial role in macrophage polarization and the progression of atherosclerosis. Herein, we provide a comprehensive review of the essential role of metabolic and epigenetic regulation, as well as the crosstalk between the two in regulating macrophage polarization in atherosclerosis. We also highlight the potential therapeutic strategies of regulating macrophage polarization via epigenetic and metabolic modifications for atherosclerosis, and offer recommendations to advance our knowledge of the roles of metabolic-epigenetic crosstalk in macrophage polarization in the context of atherosclerosis. Fundamental studies that elucidate the mechanisms by which metabolic and epigenetic regulation of macrophage polarization influence atherosclerosis will pave the way for novel therapeutic approaches.

Vulnerable plaques, which are high-risk features of atherosclerosis, constitute critical elements in the disease's progression due to their formation and rupture. Macrophages and macrophage-derived foam cells are pivotal in inducing vulnerability within atherosclerotic plaques. Thus, understanding macrophage contributions to vulnerable plaques is essential for advancing the comprehension of atherosclerosis and devising novel therapeutic and diagnostic strategies. This review provides an overview of the pathological characteristics of vulnerable plaques, emphasizes macrophages' critical role, and discusses advanced strategies for their diagnosis and treatment. It aims to present a comprehensive macrophage-centered perspective for addressing vulnerable plaques in atherosclerosis.

The metabolic interplay between macrophages and cancer cells mirrors the plasticity of both kinds of cells, which adapt to the microenvironment by sustaining cell growth and proliferation. In this way, cancer cells induce macrophage polarization, and, on the other hand, tumor-associated macrophages (TAMs) contribute to the survival of cancer cells. In a simplified manner, macrophages can assume two opposite subtypes: M1, pro-inflammatory and anti-tumor phenotype, and M2, anti-inflammatory and protumor phenotype. How do cancer cells induce macrophage polarization? Any actor involved in tumor growth, including the mitochondria, releases molecules into the tumor microenvironment (TME) that trigger a subtype transition. These metabolic changes are the primary cause of this polarization. Hepatocellular carcinoma (HCC), the prevalent type of liver primary tumor, is characterized by cells with extensive metabolic adaptions due to high flexibility in different environmental conditions. This review focuses on the main metabolic features of M1 and M2 macrophages and HCC cells underlying their metabolic behavior in response to TME.

Numerous viruses that propagate through the respiratory tract may be initially engulfed by macrophages (Mφs) within the alveoli, where they complete their first replication cycle and subsequently infect the adjacent epithelial cells. This process can lead to significant pathological damage to tissues and organs, leading to various diseases. As essential components in host antiviral immune systems, Mφs can be polarized into pro-inflammatory M1 Mφs or anti-inflammatory M2 Mφs, a process involving multiple signaling pathways and molecular mechanisms that yield diverse phenotypic and functional features in response to various stimuli. In general, when infected by a virus, M1 macrophages secrete pro-inflammatory cytokines to play an antiviral role, while M2 macrophages play an anti-inflammatory role to promote the replication of the virus. However, recent studies have shown that some viruses may exhibit the opposite trend. Viruses have evolved various strategies to disrupt Mφ polarization for efficient replication and transmission. Notably, various factors, such as mechanical softness, the altered pH value of the endolysosomal system, and the homeostasis between M1/M2 Mφs populations, contribute to crucial events in the viral replication cycle. Here, we summarize the regulation of Mφ polarization, virus-induced alterations in Mφ polarization, and the antiviral mechanisms associated with these changes. Collectively, this review provides insights into recent advances regarding Mφ polarization in host antiviral immune responses, which will contribute to the development of precise prevention strategies as well as management approaches to disease incidence and transmission.

Rupture of advanced carotid atherosclerotic plaques increases the risk of ischaemic stroke, which has significant global morbidity and mortality rates. However, the specific characteristics of immune cells with dysregulated function and proven biomarkers for the diagnosis of atherosclerotic plaque progression remain poorly characterised. Our study elucidated the role of immune cells and explored diagnostic biomarkers in advanced plaque progression using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis. We identified a subcluster of monocytes with significantly increased infiltration in the advanced plaques. Based on the monocyte signature and machine-learning approaches, we accurately distinguished advanced plaques from early plaques, with an area under the curve (AUC) of 0.899 in independent external testing. Using microenvironment cell populations (MCP) counter and non-negative matrix factorisation, we determined the association between monocyte signatures and immune cell infiltration as well as the heterogeneity of the patient. Finally, we constructed a convolutional neural network deep learning model based on gene-immune correlation, which achieved an AUC of 0.933, a sensitivity of 92.3%, and a specificity of 87.5% in independent external testing for diagnosing advanced plaques. Our findings on unique subpopulations of monocytes that contribute to carotid plaque progression are crucial for the development of diagnostic tools for clinical diseases.

Although the pathological significance of myeloid cell heterogeneity is still poorly understood, new evidence indicates that distinct macrophage subsets are characterized by specific metabolic programs that influence disease onset and progression. Within this scenario, distinct subsets of macrophages, endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), play critical roles in physiologic and pathological conditions. Of relevance, the substrates of HO-1 activity are the heme groups that derive from cellular catabolism and are converted into carbon monoxide (CO), biliverdin and Fe2+, which together elicit anti-apoptotic, anti-inflammatory activities and control oxidative damage. While high levels of expression of HO-1 enzyme by specialized macrophage populations (erythrophagocytes) guarantee the physiological disposal of senescent red blood cells (i.e. erythrocateresis), the action of HO-1 takes on pathological significance in various diseases, and abnormal CO metabolism has been observed in cancer, hematological diseases, hypertension, heart failure, inflammation, sepsis, neurodegeneration. Modulation of heme catabolism and CO production is therefore a feasible therapeutic opportunity in various diseases. In this review we discuss the role of HO-1 in different pathological contexts (i.e. cancer, infections, cardiovascular, immune-mediated and neurodegenerative diseases) and highlight new therapeutic perspectives on the modulation of the enzymatic activity of HO-1.

Atherosclerosis serves as the primary catalyst for numerous cardiovascular diseases. Growing evidence suggests that the immune response is involved in every stage of atherosclerotic plaque evolution. Rapid, but not specific, innate immune arms, including neutrophils, monocytes/macrophages, dendritic cells (DCs) and other innate immune cells, as well as pattern-recognition receptors and various inflammatory mediators, contribute to atherogenesis. The specific adaptive immune response, governed by T cells and B cells, antibodies, and immunomodulatory cytokines potently regulates disease activity and progression. In the inflammatory microenvironment, the heterogeneity of leukocyte subpopulations plays a very important regulatory role in plaque evolution. With advances in experimental techniques, the fine mechanisms of immune system involvement in atherosclerotic plaque evolution are becoming known. In this review, we examine the critical immune responses involved in atherosclerotic plaque evolution, in particular, looking at atherosclerosis from the perspective of evolutionary immunobiology. A comprehensive understanding of the interplay between plaque evolution and plaque immunity provides clues for strategically combating atherosclerosis.

Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of 18F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether 18F-FDG and 18F-NaF uptake was predictive of abdominal aortic aneurysm expansion.

Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with 18F-FDG and 18F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl2 or saline stimulation. In the 1-week cohort (n=25), the correlation between 18F-FDG or 18F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential 18F-FDG and 18F-NaF uptake or calcification volume was examined.

In the 1-week cohort, the maximum standard unit value of 18F-FDG and 18F-NaF uptake correlated with CD68- (r=0.82; P=0.001) and von Kossa staining-positive areas (r=0.89; P<0.001), respectively. In the time course cohort, 18F-FDG and 18F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, 18F-FDG showed high uptake at weeks 1 and 2, whereas a high 18F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with 18F-FDG and 18F-NaF uptake and calcification volume, especially at 1 and 2 weeks (18F-NaF [1 week]: r=0.61, 18F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; P<0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with 18F-NaF uptake at 1 week being the strongest predictor.

The uptake of 18F-NaF and 18F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with 18F-NaF uptake being the strongest predictor.

Macrophages are a dynamic cell type of the immune system implicated in the pathophysiology of vascular diseases and are a major contributor to pathological inflammation. Excessive macrophage accumulation, activation, and polarization is observed in aortic aneurysm (AA), atherosclerosis, and pulmonary arterial hypertension. In general, macrophages become activated and polarized to a pro-inflammatory phenotype, which dramatically changes cell behavior to become pro-inflammatory and infiltrative. These cell types become cumbersome and fail to be cleared by normal mechanisms such as autophagy. The result is a hyper-inflammatory environment causing the recruitment of adjacent cells and circulating immune cells to further augment the inflammatory response. In AA, this leads to excessive ECM degradation and chemokine secretion, ultimately causing macrophages to dominate the immune cell landscape in the aortic wall. In atherosclerosis, monocytes are recruited to the vascular wall, where they polarize to the pro-inflammatory phenotype and induce inflammatory pathway activation. This leads to the development of foam cells, which significantly contribute to neointima and necrotic core formation in atherosclerotic plaques. Pro-inflammatory macrophages, which affect other vascular diseases, present with fragmented mitochondria and corresponding metabolic dysfunction. Targeting macrophage mitochondrial dynamics has proved to be an exciting potential therapeutic approach to combat vascular disease. This review will summarize mitochondrial and metabolic mechanisms of macrophage activation, polarization, and accumulation in vascular diseases.

Bordetella pertussis infects the upper airways of humans and disarms host defense by the potent immuno-subversive activities of its pertussis (PT) and adenylate cyclase (CyaA) toxins. CyaA action near-instantly ablates the bactericidal activities of sentinel CR3-expressing myeloid phagocytes by hijacking cellular signaling pathways through the unregulated production of cAMP. Moreover, CyaA-elicited cAMP signaling also inhibits the macrophage colony-stimulating factor (M-CSF)-induced differentiation of incoming inflammatory monocytes into bactericidal macrophages. We show that CyaA/cAMP signaling via protein kinase A (PKA) downregulates the M-CSF-elicited expression of monocyte receptors for transferrin (CD71) and hemoglobin-haptoglobin (CD163), as well as the expression of heme oxygenase-1 (HO-1) involved in iron liberation from internalized heme. The impact of CyaA action on CD71 and CD163 levels in differentiating monocytes is largely alleviated by the histone deacetylase inhibitor trichostatin A (TSA), indicating that CyaA/cAMP signaling triggers epigenetic silencing of genes for micronutrient acquisition receptors. These results suggest a new mechanism by which B. pertussis evades host sentinel phagocytes to achieve proliferation on airway mucosa.IMPORTANCETo establish a productive infection of the nasopharyngeal mucosa and proliferate to sufficiently high numbers that trigger rhinitis and aerosol-mediated transmission, the pertussis agent Bordetella pertussis deploys several immunosuppressive protein toxins that compromise the sentinel functions of mucosa patrolling phagocytes. We show that cAMP signaling elicited by very low concentrations (22 pM) of Bordetella adenylate cyclase toxin downregulates the iron acquisition systems of CD14+ monocytes. The resulting iron deprivation of iron, a key micronutrient, then represents an additional aspect of CyaA toxin action involved in the inhibition of differentiation of monocytes into the enlarged bactericidal macrophage cells. This corroborates the newly discovered paradigm of host defense evasion mechanisms employed by bacterial pathogens, where manipulation of cellular cAMP levels blocks monocyte to macrophage transition and replenishment of exhausted phagocytes, thereby contributing to the formation of a safe niche for pathogen proliferation and dissemination.

Ferroptosis is a novel form of cell demise characterized primarily by the reduction of trivalent iron to divalent iron, leading to the release of reactive oxygen species (ROS) and consequent induction of intense oxidative stress. In atherosclerosis (AS), highly accumulated lipids are modified by ROS to promote the formation of lipid peroxides, further amplifying cellular oxidative stress damage to influence all stages of atherosclerotic development. Macrophages are regarded as pivotal executors in the progression of AS and the handling of iron, thus targeting macrophage iron metabolism holds significant guiding implications for exploring potential therapeutic strategies against AS. In this comprehensive review, we elucidate the potential interplay among iron overload, inflammation, and lipid dysregulation, summarizing the potential mechanisms underlying the suppression of AS by alleviating iron overload. Furthermore, the application of Traditional Chinese Medicine (TCM) is increasingly widespread. Based on extant research and the pharmacological foundations of active compounds of TCM, we propose alternative therapeutic agents for AS in the context of iron overload, aiming to diversify the therapeutic avenues.

Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap.

Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments.

In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa β) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes.

CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.

The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.

Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis, and has been becoming the leading cause of liver-related morbidity and mortality worldwide. Unfortunately, the pathogenesis of NASH has not been completely clarified, and there are no approved therapeutic drugs. Recent accumulated evidences have revealed the involvement of macrophage in the regulation of host liver steatosis, inflammation and fibrosis, and different phenotypes of macrophages have different metabolic characteristics. Therefore, targeted regulation of macrophage immunometabolism may contribute to the treatment and prognosis of NASH. In this review, we summarized the current evidences of the role of macrophage immunometabolism in NASH, especially focused on the related function conversion, as well as the strategies to promote its polarization balance in the liver, and hold promise for macrophage immunometabolism-targeted therapies in the treatment of NASH.

The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.

Macrophages are highly plastic cells ubiquitous in various tissues, where they perform diverse functions. They participate in the response to pathogen invasion and inflammation resolution following the immune response, as well as the maintenance of homeostasis and proper tissue functions. Macrophages are generally considered long-lived cells with relatively strong resistance to numerous cytotoxic factors. On the other hand, their death seems to be one of the principal mechanisms by which macrophages perform their physiological functions or can contribute to the development of certain diseases. In this review, we scrutinize three distinct pro-inflammatory programmed cell death pathways - pyroptosis, necroptosis, and ferroptosis - occurring in macrophages under specific circumstances, and explain how these cells appear to undergo dynamic yet not always final changes before ultimately dying. We achieve that by examining the interconnectivity of these cell death types, which in macrophages seem to create a coordinated and flexible system responding to the microenvironment. Finally, we discuss the complexity and consequences of pyroptotic, necroptotic, and ferroptotic pathway induction in macrophages under two pathological conditions - atherosclerosis and cancer. We summarize damage-associated molecular patterns (DAMPs) along with other microenvironmental factors, macrophage polarization states, associated mechanisms as well as general outcomes, as such a comprehensive look at these correlations may point out the proper methodologies and potential therapeutic approaches.

The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is largely attributed to monocyte/macrophage functions, which respond to various stimuli in the plaque microenvironment. To this end, macrophages play a central role in atherosclerotic lesions through the uptake of oxidized low-density lipoprotein that gets trapped in the artery wall, and the induction of an inflammatory response that can differentially affect the stability of the plaque in men and women. In this environment, macrophages can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, which represent the extremes of the polarization spectrum that include Mhem, M(Hb), Mox, and M4 populations. However, this traditional macrophage model paradigm has been redefined to include numerous immune and nonimmune cell clusters based on in-depth unbiased single-cell approaches. The goal of this review is to highlight (1) the phenotypic and functional properties of monocyte subsets in the circulation, and macrophage populations in atherosclerotic plaques, as well as their contribution towards stable or unstable phenotypes in men and women, and (2) single-cell RNA sequencing studies that have advanced our knowledge of immune, particularly macrophage signatures present in the atherosclerotic niche. We discuss the importance of performing high-dimensional approaches to facilitate the development of novel sex-specific immunotherapies that aim to reduce the risk of cardiovascular events.

Cardiovascular diseases (CVDs), which stand as the primary contributors to illness and death on a global scale, include vital risk factors like hyperlipidemia, hypertension, diabetes, and smoking, to name a few. However, conventional cardiovascular risk factors offer only partial insight into the complexity of CVDs. Lately, a growing body of research has illuminated that the gut microbiome and its by-products are also of paramount importance in the initiation and progression of CVDs. The gastrointestinal tract houses trillions of microorganisms, commonly known as gut microbiota, that metabolize nutrients, yielding substances like trimethylamine-N-oxide (TMAO), bile acids (BAs), short-chain fatty acids (SCFAs), indoxyl sulfate (IS), and so on. Strategies aimed at addressing these microbes and their correlated biological pathways have shown promise in the management and diagnosis of CVDs. This review offers a comprehensive examination of how the gut microbiota contributes to the pathogenesis of CVDs, particularly atherosclerosis, hypertension, heart failure (HF), and atrial fibrillation (AF), explores potential underlying mechanisms, and highlights emerging therapeutic prospects in this dynamic domain.

Phytochemicals are natural plant-derived products that provide significant nutrition, essential biomolecules, and flavor as part of our diet. They have long been known to confer protection against several diseases via their anti-inflammatory, immune-regulatory, anti-microbial, and several other properties. Deciphering the role of phytochemicals in the prevention, inhibition, and treatment of cancer-unrestrained cell proliferation due to the loss of tight regulation on cell growth and replication-has been the focus of recent research. Particularly, the immunomodulatory role of phytochemicals, which is pivotal in unchecked cell proliferation and metastasis, has recently been studied extensively. The immune system is a critical component of the tumor microenvironment, and it plays essential roles in both preventing and promoting oncogenesis. Immunomodulation includes stimulation, amplification, or inactivation of some stage(s) of the immune response. Phytochemicals and their products have demonstrated immune regulation, such as macrophage migration, nitric oxide synthase inhibition, lymphocyte, T-cell, and cytokine stimulation, natural killer cell augmentation, and NFκB, TNF, and apoptosis regulation. There is a dearth of extensive accounts of the immunomodulatory effects of phytochemicals in cancer; thus, we have compiled these effects with mechanistic aspects of dietary phytochemicals in cancer, highlighting promising candidates and ongoing clinical trials on immunotherapeutic strategies to mitigate oncogenesis.

Platelets are key vascular effectors in hemostasis, with activation signals leading to fast recruitment, aggregation, and clot formation. The canonical process of hemostasis is well-characterized and shares many similarities with pathological thrombus formation. However, platelets are also crucially involved in the maintenance of vascular integrity under both steady-state and inflammatory conditions by ensuring blood vessel homeostasis and preventing microbleeds. In these settings, platelets use distinct receptors, signaling pathways, and ensuing effector functions to carry out their deeds. Instead of simply forming clots, they mainly act as individual sentinels that swiftly adapt their behavior to the local microenvironment. In this review, we summarize previously recognized and more recent studies that have elucidated how anucleate, small platelets manage to maintain vascular integrity when faced with challenges of infection, sterile inflammation, and even malignancy. We dissect how platelets are recruited to the vascular wall, how they identify sites of injury, and how they prevent hemorrhage as single cells. Furthermore, we discuss mechanisms and consequences of platelets' interaction with leukocytes and endothelial cells, the relevance of adhesion as well as signaling receptors, in particular immunoreceptor tyrosine-based activation motif receptors, and cross talk with the coagulation system. Finally, we outline how recent insights into inflammatory hemostasis and vascular integrity may aid in the development of novel therapeutic strategies to prevent hemorrhagic events and vascular dysfunction in patients who are critically ill.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.

Short-chain fatty acids (SCFAs) derived from the fermentation of carbohydrates by gut microbiota play a crucial role in regulating host physiology. Among them, acetate, propionate, and butyrate are key players in various biological processes. Recent research has revealed their significant functions in immune and inflammatory responses. For instance, butyrate reduces the development of interferon-gamma (IFN-γ) generating cells while promoting the development of regulatory T (Treg) cells. Propionate inhibits the initiation of a Th2 immune response by dendritic cells (DCs). Notably, SCFAs have an inhibitory impact on the polarization of M2 macrophages, emphasizing their immunomodulatory properties and potential for therapeutics. In animal models of asthma, both butyrate and propionate suppress the M2 polarization pathway, thus reducing allergic airway inflammation. Moreover, dysbiosis of gut microbiota leading to altered SCFA production has been implicated in prostate cancer progression. SCFAs trigger autophagy in cancer cells and promote M2 polarization in macrophages, accelerating tumor advancement. Manipulating microbiota- producing SCFAs holds promise for cancer treatment. Additionally, SCFAs enhance the expression of hypoxia-inducible factor 1 (HIF-1) by blocking histone deacetylase, resulting in increased production of antibacterial effectors and improved macrophage-mediated elimination of microorganisms. This highlights the antimicrobial potential of SCFAs and their role in host defense mechanisms. This comprehensive review provides an in-depth analysis of the latest research on the functional aspects and underlying mechanisms of SCFAs in relation to macrophage activities in a wide range of diseases, including infectious diseases and cancers. By elucidating the intricate interplay between SCFAs and macrophage functions, this review aims to contribute to the understanding of their therapeutic potential and pave the way for future interventions targeting SCFAs in disease management.

Acute coronary syndromes due to atherosclerotic coronary artery disease are a leading cause of morbidity and mortality worldwide. Intra-plaque hemorrhage (IPH), caused by disruption of intra-plaque leaky microvessels, is one of the major contributors of plaque progression, causing a sudden increase in plaque volume and eventually plaque destabilization. IPH and its healing processes are highly complex biological events that involve interactions between multiple types of cells in the plaque, including erythrocyte, macrophages, vascular endothelial cells and vascular smooth muscle cells. Recent investigations have unveiled detailed molecular mechanisms by which IPH leads the development of high-risk "vulnerable" plaque. Current advances in clinical diagnostic imaging modalities, such as magnetic resonance image and intra-coronary optical coherence tomography, increasingly allow us to identify IPH in vivo. To date, retrospective and prospective clinical trials have revealed the significance of IPH as detected by various imaging modalities as a reliable prognostic indicator of high-risk plaque. In this review article, we discuss recent advances in our understanding for the significance of IPH on the development of high-risk plaque from basic to clinical points of view.

The gut microbiome has emerged as a crucial player in developing and progressing cardiovascular diseases (CVDs). Recent studies have highlighted the role of microbial metabolites in modulating immune cell function and their impact on CVD. Macrophages, which have a significant function in the pathogenesis of CVD, are very vulnerable to the effects of microbial metabolites. Microbial metabolites, such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), have been linked to atherosclerosis and the regulation of immune functions. Butyrate has been demonstrated to reduce monocyte migration and inhibit monocyte attachment to injured endothelial cells, potentially contributing to the attenuation of the inflammatory response and the progression of atherosclerosis. On the other hand, TMAO, another compound generated by gut bacteria, has been linked to atherosclerosis due to its impact on lipid metabolism and the accumulation of cholesterol in macrophages. Indole-3-propionic acid, a tryptophan metabolite produced solely by microbes, has been found to promote the development of atherosclerosis by stimulating macrophage reverse cholesterol transport (RCT) and raising the expression of ABCA1. This review comprehensively discusses how various microbiota-produced metabolites affect macrophage polarization, inflammation, and foam cell formation in CVD. We also highlight the mechanisms underlying these effects and the potential therapeutic applications of targeting microbial metabolites in treating CVD.

Extracellular vesicles (EVs) can be produced from red blood cells (RBCs) on a large scale and used to deliver therapeutic payloads efficiently. However, not much is known about the native biological properties of RBCEVs. Here, we demonstrate that RBCEVs are primarily taken up by macrophages and monocytes. This uptake is an active process, mediated mainly by endocytosis. Incubation of CD14+ monocytes with RBCEVs induces their differentiation into macrophages with an Mheme-like phenotype, characterized by upregulation of heme oxygenase-1 (HO-1) and the ATP-binding cassette transporter ABCG1. Moreover, macrophages that take up RBCEVs exhibit a reduction in surface CD86 and decreased secretion of TNF-α under inflammatory stimulation. The upregulation of HO-1 is attributed to heme derived from haemoglobin in RBCEVs. Heme is released from internalized RBCEVs in late endosomes and lysosomes via the heme transporter, HRG1. Consequently, RBCEVs exhibit the ability to attenuate foam cell formation from oxidized low-density lipoproteins (oxLDL)-treated macrophages in vitro and reduce atherosclerotic lesions in ApoE knockout mice on a high-fat diet. In summary, our study reveals the uptake mechanism of RBCEVs and their delivery of heme to macrophages, suggesting the potential application of RBCEVs in the treatment of atherosclerosis.

The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease (CVD), is conceptualised as a lipid-driven inflammation where macrophages play a non-redundant role. However, evidence emerging so far from single cell atlases suggests a dichotomy between lipid associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining scRNASeq of human surgical carotid endarterectomies in a discovery cohort with bulk RNASeq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project-CPIP), we reveal the existence of PLIN2hi/TREM1hi macrophages as a toll-like receptor-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for CVD.