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Macrophage-derived KIF13B acts as a potential therapeutic target in atherosclerosis by enhancing MERTK-mediated efferocytosis [scRNA-Seq]

ABSTRACT: Atherosclerosis is a chronic inflammatory disorder with high morbidity and mortality rates worldwide. Emerging evidence has reported that Kinesin family member 13b (KIF13B), a crucial motor protein, integrates hepatic lipid metabolism and inflammatory response to protect liver disease. However, the relationship between KIF13B and atherosclerosis remains unknown. The present study aimed to elucidate the specific role of KIF13B in atherosclerosis and its potential therapeutic significance.

ORGANISM(S): Mus musculus

PROVIDER: GSE298574 | GEO | 2025/06/30

REPOSITORIES: GEO

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Macrophage-derived KIF13B acts as a potential therapeutic target in atherosclerosis by enhancing MERTK-mediated efferocytosis [RNA-Seq]

Project description:Atherosclerosis is a chronic inflammatory disorder with high morbidity and mortality rates worldwide. Emerging evidence has reported that Kinesin family member 13b (KIF13B), a crucial motor protein, integrates hepatic lipid metabolism and inflammatory response to protect liver disease. However, the relationship between KIF13B and atherosclerosis remains unknown. The present study aimed to elucidate the specific role of KIF13B in atherosclerosis and its potential therapeutic significance.

2025-06-30 | GSE298492 | GEO

Macrophage-derived KIF13B acts as a potential therapeutic target in atherosclerosis by enhancing MERTK-mediated efferocytosis [RNA-Seq]

Project description:Macrophage-derived KIF13B acts as a potential therapeutic target in atherosclerosis by enhancing MERTK-mediated efferocytosis [RNA-Seq]

| PRJNA1269541 | ENA

Macrophage-derived KIF13B acts as a potential therapeutic target in atherosclerosis by enhancing MERTK-mediated efferocytosis [scRNA-Seq]

Project description:Macrophage-derived KIF13B acts as a potential therapeutic target in atherosclerosis by enhancing MERTK-mediated efferocytosis [scRNA-Seq]

| PRJNA1269963 | ENA

Vascular Smooth Muscle Cell-derived KIF13B Protects Against Atherosclerosis: Evidence from Humans and Mice

Project description:Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide, with plaque instability being a major culprit. Phenotypic switching of vascular smooth muscle cells (VSMCs), the most abundant cell type in the vascular wall, is a central event in atherosclerosis, driving both plaque progression and stability, yet the underlying mechanisms are incompletely understood, limiting drug development targeting this process. Kinesin family member 13B (KIF13B) has been implicated in vascular biology, but its function in VSMCs is unknown. Here, we demonstrate that VSMC-specific deletion of Kif13b in mice overexpressed with proprotein convertase subtilisin/kexin type 9 exacerbated lesion development and impaired plaque stability, characterized by thinner fibrous caps and increased inflammation. Mechanistically, we identified that KIF13B facilitates the Potassium channel tetramerization domain containing 10 (KCTD10)-dependent ubiquitination and proteasomal degradation of Krüppel-like factor 4 (KLF4), a key driver of pathogenic VSMC transition. This KIF13B/KCTD10 axis constrains KLF4 protein levels, thereby inhibiting pro-inflammatory, fibroblast-like VSMC transition and preserving the contractile phenotype. Importantly, the adverse effects of Kif13b deficiency on atherogenesis were effectively rescued by the small-molecule KLF4 inhibitor Kenpaullone. Our results unveil a novel VSMC-specific atheroprotective role for KIF13B, define the KIF13B/KCTD10/KLF4 pathway as a key regulatory axis governing VSMC fate and plaque stability, and validate its therapeutic potential for treating advanced atherosclerosis.

2026-01-01 | GSE314838 | GEO

Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis

Project description:Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also comprises enhanced injury resolution capacity to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) pre-challenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis, and functional assays showed greater capacity of trained AMs to efferocytosis of cellular- debris, and facilitate injury resolution. Single-cell high-dimensional mass-cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AMs subset with pro-resolving phenotypes. Training epigenetically reprogrammed AMs to express a higher level of the transcription factor KLF4 which in turn upregulates the efferocytosis receptor MERTK. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal Pseudomonas aeruginosa. Thus, our study has identified a unique subset of tissue-resident trained macrophages which prevent hyper-inflammation and restore tissue homeostasis following pathogen challenge.

2023-08-16 | GSE231217 | GEO

IRF5 siRNA Nano-Immunotherapy: Restoring Macrophage Efferocytosis in Atherosclerosis

Project description:We observe that the siIRF5 nano-immunotherapeutics were efficiently taken up by lesional macrophages, particularly Cd11c+ and Trem2hi macrophages, and enhanced their phagocytic clearance of apoptotic cells by efficiently silencing IRF5 expression within these macrophage subsets in atherosclerotic plaques. This resulted in remarkable therapeutic efficacy, as evidence by reduction of necrotic core area and enhancement of plaque stability in two independent ApoE-/- murine models of atherosclerosis. Mechanistically, single-cell RNA sequencing analysis revealed that siIRF5 nano-immunotherapeutics increased the pro-efferocytic receptors while decreasing the expression of pro-inflammatory genes associated with cytokine and chemokine pathways in lesional macrophages.

2025-08-14 | GSE301529 | GEO

NOX2 inhibition stabilizes vulnerable plaques by enhancing macrophage efferocytosis via MertK/PI3K/AKT pathway.

Project description:NADPH oxidases 2 (NOX2) is the main source of ROS in macrophages, which plays a critical role in the formation of atherosclerosis. However, effects of NOX2 inhibition on established vulnerable plaques and the potential role involved remain unclear. The purpose of this study is to investigate the latent mechanism of NOX2-triggered vulnerable plaque development. We generated a vulnerable carotid plaque model induced by carotid branch ligation and renal artery constriction, combined with a high-fat diet in ApoE-/- mice. NOX2 specific inhibitor, GSK2795039 (10 mg/kg/day by intragastric administration for 8 weeks) significantly prevented vulnerable plaque, evaluated by micro-ultrasound imaging parameters. A profile of less intraplaque hemorrhage detection, increased collagen-lipid ratio, fibrous cap thickness and less necrotic core formation were also found in GSK2795039 treated group. Mechanistically, reduced 4-HNE, in situ lesional apoptosis and enhanced efferocytosis were involved in mice treated with NOX2 inhibitor. Further analysis in mouse macrophages confirmed the role of NOX2 inhibition in enhancing macrophage efferocytosis by regulating the MertK/PI3K/AKT pathway. In summary, our data defined previously few recognized roles of NOX2 in vulnerable plaque pathogenesis and an undescribed NOX2-ROS-MerTK axis acts involved in regulating macrophage efferocytosis in the formation of rupture-prone vulnerable plaques.

| S-EPMC10320254 | biostudies-literature

Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis [RNA-seq]

2023-08-16 | GSE231218 | GEO

DBA/2J Haplotype on Distal Chromosome 2 Reduces Mertk Expression, Restricts Efferocytosis, and Increases Susceptibility to Atherosclerosis.

Project description:ObjectiveArch atherosclerosis 4 (Aath4) is a quantitative trait locus for atherosclerotic plaque formation in the inner curve of the aortic arch previously identified in an F2 cross of Apoe-/- mice on DBA/2J and 129S6 backgrounds. C-mer proto-oncogene tyrosine kinase (Mertk), coding for a ligand-activated transmembrane tyrosine kinase, is a candidate gene within the same chromosomal region. Our objective was to determine whether strain differences in Mertk influence plaque formation.Approach and resultsTo dissect the strain effects of Mertk on atherosclerosis, we first established a congenic mouse line (Aath4aDBA/DBA ) in which a 5' region of Aath4 of DBA/2J, including Mertk, was backcrossed onto a 129S6-Apoe-/- background. The resulting Aath4aDBA/DBA male mice developed significantly larger plaques compared with control mice (Aath4a129/129 ), proving that the DBA/2J allele of Aath4a is proatherogenic. Thioglycollate-elicited peritoneal macrophages from Aath4aDBA/DBA mice express less than 50% of Mertk mRNA and cell-surface MERTK protein compared with those from the control mice. Moreover, both large and small peritoneal Aath4aDBA/DBA macrophages showed reduced phagocytosis of apoptotic cells. When Mertk cDNAs from 129S6 and DBA/2J mice were overexpressed in HEK293T (human embryonic kidney 293T) cells, phagocytosis of apoptotic cells was equally enhanced in direct proportion to Mertk levels, indicating that phagocytosis is modulated by the amount of MERTK, but that it is not affected by MERTK amino acid differences between 129S6 and DBA/2J.ConclusionsReduced transcription of Mertk, rather than differences in MERTK protein structure, determines the reduced efficiency of apoptotic cell clearance in the Aath4aDBA/DBA mice, which, in turn, contributes to their increased susceptibility to atherosclerosis.

| S-EPMC5497749 | biostudies-literature

Trained immunity of alveolar macrophages promotes injury resolution by enhancing KLF4-MERTK-mediated efferocytosis.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-16 | GSE231219 | GEO