Dipeptidyl Peptidase 4/Midline‐1 Axis Promotes T Lymphocyte Motility in Atherosclerosis

Rao, Xiaoquan; Razavi, Michael; Mihai, Georgeta; Wei, Yingying; Braunstein, Zachary; Frieman, Matthew B.; Sun, Xiao Jian; Gong, Quan; Zhao, Gang; Liu, Zheng; Quon, Michael J.; Dong, Lingli; Rajagopalan, Sanjay; Zhong, Jixin

doi:10.1002/advs.202204194

Cited by 5 publications

(7 citation statements)

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“…Cytoskeletal rearrangement plays a crucial role in cell migration 34 and we have reported that Mid1 deletion results in disrupted cytoskeletal rearrangement and migration 24 . However, the mechanism via which Mid1 regulates cytoskeletal rearrangement and cell migration is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Mid1 -/- mice were generated using CRISPR-Cas9 technology as we previously described 24 . Rag2 -/- and CD45.1 mice were purchased from Shanghai Model Organisms Center, Inc. All the mice used in the experiment were kept in the SPF animal facilities at Tongji Hospital.…”

Section: Methodsmentioning

confidence: 99%

“…A study reported that Mid1 is highly expressed in murine killer cells and controls their degranulation process 23 . We recently showed that Mid1 mediates the promotive effect of dipeptidyl peptidase-4 on T cell migration and accelerates atherosclerosis in mice 24 . These studies indicate that Mid1 may play a key role in regulating T cell inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway

Wei,

Li,

Huang

et al. 2024

Theranostics

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Background: Effector T cell activation, migration, and proinflammatory cytokine production are crucial steps in autoimmune disorders such as multiple sclerosis (MS). While several therapeutic approaches targeting T cell activation and proinflammatory cytokines have been developed for the treatment of autoimmune diseases, there are no therapeutic agents targeting the migration of effector T cells, largely due to our limited understanding of regulatory mechanisms of T cell migration in autoimmune disease. Here we reported that midline-1 (Mid1) is a key regulator of effector T cell migration in experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. Methods: Mid1 -/- mice were generated by Crispr-Cas9 technology. T cell-specific Mid1 knockout chimeric mice were generated by adoptive transfer of Mid1 -/- T cells into lymphocyte deficient Rag2 -/- mice. Mice were either immunized with MOG 35-55 (active EAE) or received adoptive transfer of pathogenic T cells (passive EAE) to induce EAE. In vitro Transwell ® assay or in vivo footpad injection were used to assess the migration of T cells. Results: Mid1 was significantly increased in the spinal cord of wild-type ( Wt ) EAE mice and disruption of Mid1 in T cells markedly suppressed the development of both active and passive EAE. Transcriptomic and flow cytometric analyses revealed a marked reduction in effector T cell number in the central nervous system of Mid1 -/- mice after EAE induction. Conversely, an increase in the number of T cells was observed in the draining lymph nodes of Mid1 -/- mice. Mice that were adoptively transferred with pathogenic Mid1 -/- T cells also exhibited milder symptoms of EAE, along with a lower T cell count in the spinal cord. Additionally, disruption of Mid1 significantly inhibited T-cell migration both in vivo and in vitro . RNA sequencing suggests a suppression in multiple inflammatory pathways in Mid1 -/- mice, including mTOR signaling that plays a critical role in cell migration. Subsequent experiments confirmed the interaction between Mid1 and mTOR. Suppression of mTOR with rapamycin or microtubule spindle formation with colcemid blunted the regulatory effect of Mid1 on T cell migration. In addition, mTOR agonists MHY1485 and 3BDO restored the migratory deficit caused by Mid1 depletion. Conclusion: Our data suggests that Mid1 regulates effector T cell migration to the central nervous system via mTOR/microtubule pathway in EAE, and thus may serve as a potential therapeutic target for the treatment of MS. ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway

Wei,

Li,

Huang

et al. 2024

Theranostics

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“…DPP4+ chimeric antigen receptor T cells exhibited robust cytotoxicity against the DPP4+ T-cell lymphoma cells activated multiple effector functions and limited tumour progression (22). However, DPP4 de ciency reduces T-cell motility by suppressing the expression of microtubule associated protein midline-1 in T cells (23). Post-translational modi cation of chemokines mediated by DPP4 has been shown to negatively regulate lymphocyte tra cking, and its inhibition enhances T cell migration and tumor immunity (24).…”

Section: Discussionmentioning

confidence: 99%

DPP4 Promotes Papillary Thyroid Cancer Progression by Regulating the Infiltration and Exhaustion of CD8+ T cells

Jing,

Wu,

et al. 2024

Preprint

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Background: Papillary thyroid cancer (PTC) is one of the most prevalent endocrine malignancy with a rapidly increasing incidence worldwide, a special immune microenvironment of which is not well characterized. Thus, the aim of this study was to identify the key biomarkers that regulate immune cells for the development and recurrence of PTC. Methods: The expression of immune-associated differentially expressed genes (DEGs) in human PTC was examined by bioinformatics analysis of TCGA and GEO datasets. The CIBERSORT and TIMER tool was used to analyze the distribution of tumor[1]infiltrating immune cells in PTC. Furthermore, DEG expression and function for the infiltration of CD8+ T cells were explored using human PTC specimens. Results: In this study, we identified DPP4 as a key gene in PTC by differential expression analysis among four GEO datasets and TCGA dataset and validated its overexpression profile by data from the TCGA, HPA databases, WB and PCR analysis. DPP4 upregulation significantly correlated with advanced grades, stages, and poor progression-free survival.Based on TIMER and CIBERSORT analysis, DPP4 expression tightly correlated with the infiltration of diverse immune cell types, especially CD8+ T cell subtypes. Compared with benign thyroid tumor, the proportion of CD3+CD8+ T cells in peripheral blood of PTC patients was significantly decreased, while the CD3+CD8+DPP4+ T cells of PTC patients was increased. The relative expression of PD-L1 and CTLA-4 in the CD8+DPP4+ T cells of PTC patients was higher than that in the CD8+DPP4- T cells. In addition, CD8+DPP4+ T cells of PTC patients showed the lower expression of IFN-γ and increased expression of IL-13 than that in benign thyroid tumor. The relative expression of IFN-γ, TNF-α, IL-4, IL-5, and IL-13 in CD8+DPP4+ T cells were both lower than that in CD8+DPP4- T cells among PTC and benign thyroid tumor patients. Conclusion: Our work suggests that the immune-associated DEG DPP4 is upregulated in PTC tissues and is tightly correlated with clinical stages and outcomes and regulates immune infiltration, but in particular involves in CD8+ T cell evasion and exhaustion. These findings may offer a new prospect for targeting CD8+ T cell exhaustion therapies for the treatment of PTC.

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“…Cardiovascular diseases (CVDs) are the leading cause of global mortality and disability, accounting for almost half of total death annually. − Atherosclerosis (AS) is an inflammation-driven chronic disease caused by the asymptomatic buildup of plaques on the arterial wall to the formation of atherosclerotic plaque, even the rupture of plaque. , Meanwhile, macrophages play a critical role in uptaking the oxidized low density lipoprotein (ox-LDL) to deteriorate into the foam cells, simultaneously releasing various inflammatory factors and then inducing the formation of atherosclerotic plaque. , Clinical study has found that the foam cell-rich atherosclerotic plaque is prone to rupture into thrombus, inducing some fatal complications such as myocardial infarction and stroke. , Thence, it is highly important to efficiently recognize the foam cells and then precisely identify the morphology and disperse distribution of the plaques for physicians to make timely clinical decisions and perform proactive interventions as early as possible …”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species-Responsive Sequentially Targeted AIE Fluorescent Probe for Precisely Identifying the Atherosclerotic Plaques

Liu,

He,

Zhong

et al. 2023

ACS Appl. Mater. Interfaces

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The formation of atherosclerosis is the root cause of various cardiovascular diseases (CVDs). Therefore, effective CVD interventions call for precise identification of the plaques to aid in clinical treatment of such diseases. Herein, a reactive oxygen species (ROS)-responsive sequentially targeted fluorescent probe is developed for atherosclerotic plaque recognition. An aggregation-induced emission active fluorophore is linked to maleimide (polyethylene glycol) hydroxyl with a ROS-responsive cleavable bond, which is further functionalized with CLIKKPF peptide (TPAMCF) for specifically binding to phosphatidylserine of the foam cells. After being assembled in aqueous medium, TPAMCF nanoparticles can efficiently accumulate in the plaques through the high affinity of CLIKKPF to the externalized phosphatidylserine of the foam cells. Activated by the locally accumulated ROS in foam cells, the nanoparticles are interrupted, and then TPA can be released and subsequently identify the lipid droplets inside the foam cells to achieve fluorescence imaging of the plaques. Such nanoprobes have the favorable ROS response performance and exhibit a special target binding to the foam cells in vitro. In addition, nanoprobe-based fluorescence imaging permitted the high-contrast and precise detection of atherosclerosis specimens ex vivo. Therefore, as a promising fluorescent probe, TPAMCF is capable of being a potential candidate for the detection of atherosclerotic plaque.

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Dipeptidyl Peptidase 4/Midline‐1 Axis Promotes T Lymphocyte Motility in Atherosclerosis

Cited by 5 publications

References 53 publications

Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway

Midline-1 regulates effector T cell motility in experimental autoimmune encephalomyelitis via mTOR/microtubule pathway

DPP4 Promotes Papillary Thyroid Cancer Progression by Regulating the Infiltration and Exhaustion of CD8+ T cells

Reactive Oxygen Species-Responsive Sequentially Targeted AIE Fluorescent Probe for Precisely Identifying the Atherosclerotic Plaques

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