Regulation Of Leukocyte Migration Research Articles

Integrated bioinformatic analysis of the molecular mechanisms between type 2 diabetes mellitus and osteoarthritis.

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome that has been identified as an independent risk factor for osteoarthritis (OA) and may even trigger and exacerbate the progression of OA. However, the relationship between T2DM and OA is complex and has not yet been fully clarified by current research. In this study, we analyzed the potential mechanism of action between T2DM and OA by bioinformatics. Transcriptome sequencing data of T2DM (GSE25724) and OA (GSE55235) were downloaded from the gene expression omnibus. Differential expression analysis was performed for different subgroups to obtain differentially expressed genes. The protein-protein interaction network was constructed using overlapping genes and screened for hub targets. Then the enrichment analysis was performed separately for overlapping and hub targets. The GeneMANIA is used to predict functionally similar genes of hub genes. Differential expression analyses revealed that 184 genes are involved in both diseases together. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment results showed that the overlapping genes were mainly involved in the advanced glycation end products-receptor of advanced glycation end products signaling pathway, the NF-kappa B signaling pathway, the mitogen-activated protein kinases signaling pathway, and the interleukin-17 signaling pathway in diabetic complications. The functions of genes similar to the hub genes are focused on cell chemotaxis, positive regulation of cell migration, positive regulation of RNA polymerase II transcription, regulation of leukocyte migration, epithelial cell proliferation, and integrated stress response signaling. The transcription factor Jun and C-X-C motif chemokine 8 may play an important role in the inflammatory response caused by advanced glycation end products. This study improves our understanding of T2DM complicating OA and helps to stimulate more effective treatments.

Immunologic analysis of CSF in patients with de novo diagnosed RRMS. The role of chemokines in the early phase of the disease

Objectives: Multiple sclerosis (MS) is a chronic CNS autoimmune disease characterized by demyelination and neurodegeneration. Chemokines regulate leukocyte migration and inflammation in MS. In the present study, we evaluated selected chemokine levels in the cerebrospinal fluid of patients with multiple sclerosis diagnosed de novo compared to healthy controls.Methods: We measured EOTAXIN, IP-10, MCP-1, MIP-1a, MIP-1b and RANTES in the cerebrospinal fluid of 118 patients with de novo RRMS and 112 controls, analyzing correlations with time from symptom onset to diagnosis and changes in MRI.Results: Higher levels of EOTAXIN, IP-10, MIP-1B and RANTES, and lower MCP-1 were observed in MS patients compared to controls. MIP-1A did not show statistical significance. EOTAXIN and IP-10 concentrations increased with time. RANTES concentration correlated positively with T2 changes in MRI of the cervical spine, and EOTAXIN concentration correlated negatively with gadolinium (Gd+) changes in the cervical spine. There was no correlation with changes in the thoracic spine or brain.Conclusions: Chemokines play a significant role in the early phase of MS by influencing inflammatory activity. They may represent potential therapeutic targets for the treatment of this disease.

Optimized therapeutic potential of Yinchenhao decoction for cholestatic hepatitis by combined network meta-analysis and network pharmacology

BackgroundCholestatic hepatitis is recognized as a significant contributor to the development of liver fibrosis and cirrhosis. As a well-known classic formula for the treatment of cholestatic hepatitis, Yinchenhao decoction (YCHD) is widely used in countries in Asia, including China, Japan, and Korea. However, in recent years, a risk of liver injury has been reported from Rheum palmatum L. and Gardenia jasmonoides J.Ellis which are the main ingredients of YCHD. Therefore, the question arises whether YCHD is still safe enough for the treatment of cholestatic hepatitis or whether an optimized ratio of ingredients should be applied. These is inevitable questions for the clinical application of YCHD. PurposeTo provide a scientific basis for the clinical application of YCHD through a combination of meta-analysis and network pharmacology and to find the best ratio of components to ensure optimal therapeutic efficacy and safety. At the same time, a deeper understanding of the mechanisms of YCHD was explored. MethodsWe retrieved relevant trials from various databases including PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases up to August 2023. After screening for inclusion and exclusion criteria, we assessed efficiency, ALT, AST, and TBIL as outcome parameters. The relevant data underwent a network meta-analysis using STATA 16.0 software. Based on network pharmacology, we screened the disease targets, active ingredients, and targets related to YCHD. The targets were visualized using Cytoscape 3.9.1. Then, potential mechanisms were explored based on bioinformatic techniques. ResultsTwenty eligible studies were finally screened and a total of 1,591 patients who fulfilled the inclusion criteria were enrolled in the study. The meta-analysis results indicated that TG-c (treatment group c) [(Artemisia capillaris Thunb. : Gardenia jasminoides J.Ellis : Rheum palmatum L. = 10:5:2–10:5:3) + CT] was the most promising therapeutic approach, demonstrating superior efficacy and notable improvements in both AST and TBIL levels. For ALT, TG-d [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:1:1–5:2:1) + CT] exhibited the greatest potential as optimal therapy option. Based on the surface under the cumulative ranking curve (SUCRA) values, TG-c was the best therapy in terms of efficiency and improvement in TBIL levels, while TG-d was the most effective in reducing ALT levels. For AST levels, TG-e [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:2:2–5:3:3) + CT] was the most effective therapy. The comprehensive analysis revealed that TG-c exhibited the most pronounced efficacy. Combined network pharmacology, GO enrichment analysis and KEGG pathway enrichment analysis displayed that the key target genes of Artemisia capillaris, Rheum palmatum, and Gardenia jasminoides were closely involved in inflammation response, bile transport, apoptosis, oxidative stress, and regulation of leukocyte migration. Notably, bile secretion dominated the common pathway of the three herbs. On the other hand, Artemisia capillaris exhibited a unique mode of action by regulating the IL-17 signaling pathway, which may play a crucial role in its effectiveness. ConclusionBased on our findings, the optimal TG-C demonstrated the most favorable overall therapeutic efficacy by increasing the dosage of Artemisia capillaris while reducing the dosage of Gardenia jasminoides and Rheum palmatum. This is attributed to the potent ability of Artemisia capillaris. to effectively modulate the IL-17 signaling pathway, thereby exerting a beneficial therapeutic effect. Conversely, Gardenia jasminoides and Rheum palmatum may potentially enhance the activation of the NF-кB signaling pathway, thereby elevating the risk of hepatotoxicity.

Exploring the role of neutrophil extracellular traps in neuroblastoma: identification of molecular subtypes and prognostic implications.

Cancer cells induce neutrophil extracellular traps (NETs) to promote tumor progression and metastasis. However, only a few studies have focused on the role of NETs in Neuroblastoma (NB). First, based on the expression of NET-related genes, consensus clustering analysis was conducted to cluster NB samples into different subtypes. Differential analysis was performed to identify DEGs between subtypes. Functional items and related pathways of DEGs were identified using enrichment analysis. Univariate Cox analysis and the LASSO algorithm were used to identify biomarkers for prognosis. Furthermore, independent prognostic analysis was performed. Immune infiltration analysis was performed to identify differential immune cells. Finally, the verification of prognostic model genes were taken by the immunohistochemical staining and quantitative real-time PCR. Consensus clustering analysis demonstrated that NB samples were clustered into two subtypes. There were 125 DEGs between the two subtypes of NB. Moreover, the enrichment analysis results showed that the DEGs were mainly associated with 'external side of plasma membrane,' 'immune receptor activity' 'regulation of leukocyte migration' GO items. There were also several GO items related to neutrophils, such as regulation of neutrophil migration and differentiation. KEGG pathways revealed that the DEGs were correlated with in immunity-related activities, including 'Complement and coagulation cascades,' 'Neutrophil extracellular trap formation, 'T cell receptor signaling pathway,' 'PD-L1 expression and PD-1 checkpoint pathway in cancer' and so on. A total of five biomarkers,[Selenoprotein P1 (SEPP1), Fibrinogen-like protein 2 (FGL2), NK cell lectin-like receptor K1 (KLRK1), ATP-binding cassette transporters 6(ABCA6) and Galectins(GAL)], were screened, and a risk model based on the biomarkers was created. Furthermore, a nomogram for forecasting the survival rates of patients with NB was established based on the risk score, age at diagnosis, and MYCN status. Eight differential immune cells (CD8 + T cells, resting mast cells, etc.) were acquired between the two risk subgroups. The expression levels of five prognostic model genes at the protein and mRNA were verified and all results were consistent with the results of our bioinformatics analysis. We initially found that five NET-related genes were significantly differentially expressed in NETs-associated molecular isoforms and two Netrg molecular isoforms were found to be associated with poorer prognosis. This stratification might provide insight into the prediction of prognosis and ideal immunotherapy strategies for patients with NB. However, we also noted that the formation of NETs is a complex biological process involving the regulation of multiple cytokines and cellular interactions. Therefore, the exact roles of these genes and their specific mechanisms in the formation of NETs and the development of NB still need to be further investigated.

Unveiling the bioinformatic genes and their involved regulatory mechanisms in type 2 diabetes combined with osteoarthritis.

Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are both prevalent diseases that significantly impact the health of patients. Increasing evidence suggests that there is a big correlation between T2D and OA, but the molecular mechanisms remain elusive. The aims of this study are to investigate the shared biomarkers and potential molecular mechanisms in T2D combined with OA. T2D and OA-related differentially expressed genes (DEGs) were identified via bioinformatic analysis on Gene Expression Omnibus (GEO) datasets GSE26168 and GSE114007 respectively. Subsequently, extensive target prediction and network analysis were finished with Gene Ontology (GO), protein-protein interaction (PPI), and pathway enrichment with DEGs. The transcription factors (TFs) and miRNAs coupled in co-expressed DEGs involved in T2D and OA were predicted as well. The key genes expressed both in the clinical tissues of T2D and OA were detected with western blot and qRT-PCR assay. Finally, the most promising candidate compounds were predicted with the Drug-Gene Interaction Database (DGIdb) and molecular docking. In this study, 209 shared DEGs between T2D and OA were identified. Functional analysis disclosed that these DEGs are predominantly related to ossification, regulation of leukocyte migration, extracellular matrix (ECM) structural constituents, PI3K/AKT, and Wnt signaling pathways. Further analysis via Protein-Protein Interaction (PPI) analysis and validation with external datasets emphasized MMP9 and ANGPTL4 as crucial genes in both T2D and OA. Our findings were validated through qRT-PCR and Western blot analyses, which indicated high expression levels of these pivotal genes in T2D, OA, and T2D combined with OA cases. Additionally, the analysis of Transcription Factors (TFs)-miRNA interactions identified 7 TFs and one miRNA that jointly regulate these important genes. The Receiver Operating characteristic (ROC) analysis demonstrated the significant diagnostic potential of MMP9 and ANGPTL4.Moreover, we identified raloxifene, ezetimibe, and S-3304 as promising agents for patients with both T2D and OA. This study uncovers the shared signaling pathways, biomarkers, potential therapeutics, and diagnostic models for individuals suffering from both T2D and OA. These findings not only present novel perspectives on the complex interplay between T2D and OA but also hold significant promise for improving the clinical management and prognosis of patients with this concurrent condition.

Endoplasmic reticulum stress-related features predict the prognosis of osteosarcoma and reveal STC2 as a novel risk indicator for disease progression.

Endoplasmic reticulum (ER) stress exerts significant effects on cell growth, proliferation, migration, invasion, chemoresistance, and angiogenesis in various cancers. However, the impact of ER stress on the outcomes of osteosarcoma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TARGET) osteosarcoma dataset to reflect immune features and predict the prognosis of osteosarcoma patients. Survival analysis revealed significant differences in overall survival among osteosarcoma patients with different ER stress-related risk scores. Furthermore, ER stress-related risk features were significantly associated with the clinical pathological characteristics of osteosarcoma patients and could serve as independent prognostic indicators. Functional enrichment analysis indicated associations of the risk model with cell chemotaxis, leukocyte migration, and regulation of leukocyte migration. Additionally, the ER stress-related risk model suggested the presence of an immunosuppressive microenvironment and immune checkpoint responses. We validated the significance of 7 ER stress-related genes obtained from LASSO regression analysis through RT-qPCR testing on osteosarcoma samples from a local hospital, and inferred the importance of STC2 based on the literature. Subsequently, IHC experiments using samples from 70 osteosarcoma cases and 21 adjacent tissue samples confirmed differential expression of STC2 between cancer and normal tissues, and explored the gene's expression in pan-cancer and its association with clinical pathological parameters of osteosarcoma. In conclusion, we have proposed an ER stress risk model as an independent prognostic factor and identified STC2 as a novel risk indicator for disease progression, providing a promising direction for further research and treatment of osteosarcoma.

The Chemokine, CCL20, and Its Receptor, CCR6, in the Pathogenesis and Treatment of Psoriasis and Psoriatic Arthritis.

Chemokines represent a superfamily of immune-modulatory small protein molecules that regulate leukocyte migration to inflammatory sites through their chemoattractant and cell signaling properties. This review focuses on the immunological functions of the CCR6 chemokine receptor and is chemokine ligand, CCL20, that contribute to it role in inflammation in human psoriasis. Peer-reviewed relevant articles are searched and selected from 2000 to 2022 using the search engines including PubMed and Google Scholar. After selectively reviewing and evaluating over seventy articles, a comprehensive overview on the immunology of CCL20-CCR6 axis in psoriasis and psoriatic arthritis, the X-ray crystal structures of CCL20 monomers, and the potential of developing clinical therapies targeting this axis is summarized. Over the past decade, preclinical studies carried out in animal models of psoriasis involving agents targeting CCL20-CCR6 axis have yielded promising results. Other studies that this axis may play a role in a number of other autoimmune diseases, including rheumatoid arthritis, suggesting a rationale for further investigation into this key signaling/migratory pathway.

CXCR3 deletion aggravates corneal neovascularization in a corneal alkali-burn model.

Corneal neovascularization can cause devastating consequences including vision impairment and even blindness. Corneal inflammation is a crucial factor for the induction of corneal neovascularization. Current anti-inflammatory approaches are of limited value with poor therapeutic effects. Therefore, there is an urgent need to develop new therapies that specifically modulate inflammatory pathways and inhibit neovascularization in the cornea. The interaction of chemokines and their receptors plays a key role in regulating leukocyte migration during inflammatory response. CXCR3 is essential for mediating the recruitment of activated T cells and microglia/macrophages, but the role of CXCR3 in the initiation and promotion of corneal neovascularization remains unclear. Here, we showed that the expression of CXCL10 and CXCR3 was significantly increased in the cornea after alkali burn. Compared with WT mice, CXCR3-/- mice exhibited significantly increased corneal hemangiogenesis and lymphangiogenesis after alkali burn. In addition, exaggerated leukocyte infiltration and leukostasis, and elevated expression of inflammatory cytokines and angiogenic factor were also found in the corneas of CXCR3-/- mice subjected to alkali burn. With bone marrow (BM) transplantation, we further demonstrated that the deletion of CXCR3 in BM-derived leukocytes plays a key role in the acceleration of alkali burn-induced corneal neovascularization. Taken together, our results suggest that upregulation of CXCR3 does not exhibit its conventional action as a proinflammatory cytokine but instead serves as a self-protective mechanism for the modulation of inflammation and maintenance of corneal avascularity after corneal alkali burn.

CXCL10 Chemokine: A Critical Player in RNA and DNA Viral Infections.

Chemokines constitute a group of small, secreted proteins that regulate leukocyte migration and contribute to their activation. Chemokines are crucial inflammatory mediators that play a key role in managing viral infections, during which the profile of chemokine expression helps shape the immune response and regulate viral clearance, improving clinical outcome. In particular, the chemokine ligand CXCL10 and its receptor CXCR3 were explored in a plethora of RNA and DNA viral infections. In this review, we highlight the expression profile and role of the CXCL10/CXCR3 axis in the host defense against a variety of RNA and DNA viral infections. We also discuss the interactions among viruses and host cells that trigger CXCL10 expression, as well as the signaling cascades induced in CXCR3 positive cells.

Chemokines and anionic phospholipids: new binding partners for microbial killing and apoptotic cell clearance

Abstract Chemokines constitute a large family of small cytokines that regulate leukocyte migration in immunity and inflammation, some of which also have direct bacteria-killing properties. While the molecular mechanism by which chemokines kill bacteria remains poorly understood, chemokines mediate cell migration by interacting with cell surface glycosaminoglycans (GAGs) and G protein-coupled receptors (GPCRs). We have discovered that many chemokines interact with high affinity with anionic membrane phospholipids, including phosphatidylserine (PS) and cardiolipin (CL) which are selectively exposed on the membrane of apoptotic cells and apoptotic extracellular vesicles (ApoEV), and bacteria, respectively. This adds to GPCRs and GAGs a third class of cell surface binding site for chemokines and expands the scope of chemokine action to the biological niches occupied by PS and CL. For instance, we found that ApoEV induce phagocyte migration for apoptotic cell clearance by presenting PS-binding chemokines on the vesicle surface to GPCRs expressed by phagocytes. This is a novel PS-dependent mechanism for chemokine delivery by extracellular vesicles potentially relevant to other areas of immunology and indicates that chemokines may play a more prominent role in the removal of dying cells than previously reported. On the other hand, we discovered that only CL-binding chemokines are antimicrobial and that CL-deficient bacteria are resistant to chemokine treatment, indicating that chemokines kill bacteria by targeting CL on the bacterial membrane. In short, we have identified chemokines as the first family of soluble cytokines whose bioactivities can be regulated by direct interaction with membrane phospholipids. Supported by NIAID/NIH intramural research program

Neural control of immune cell trafficking.

Leukocyte trafficking between blood and tissues is an essential function of the immune system that facilitates humoral and cellular immune responses. Within tissues, leukocytes perform surveillance and effector functions via cell motility and migration toward sites of tissue damage, infection, or inflammation. Neurotransmitters that are produced by the nervous system influence leukocyte trafficking around the body and the interstitial migration of immune cells in tissues. Neural regulation of leukocyte dynamics is influenced by circadian rhythms and altered by stress and disease. This review examines current knowledge of neuro-immune interactions that regulate leukocyte migration and consequences for protective immunity against infections and cancer.

Constructing a competing endogenous RNA network for osteoarthritis.

BackgroundOsteoarthritis (OA) is one of the most common diseases in elderly people; however, the correlation between molecular alterations and the occurrence and progression of OA are still not well understood. We conducted this study to investigate the molecular changes in OA via the competing endogenous ribonucleic acid (ceRNA) network.MethodsWe downloaded the messenger RNA (mRNA) data set, GSE48556, the microRNA (miRNA) data set, GSE105027, and the long non-coding (lncRNA) data set, GSE126963 from the Gene Expression Omnibus (GEO) database, and examined the differentially expressed genes (DEGs) in these data sets. Further, we constructed a ceRNA network of the differentially expressed miRNAs, mRNAs, and lncRNAs. To determine the biological functions of the ceRNA network, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Finally, we conducted an immune cell infiltration analysisusing single-sample gene set enrichment analysis to examine the abundance of immune cells in healthy and OA patients, and compared the infiltration of 28 immune cells between the healthy and OA samples. We also analyzed the relationship between the abundance of immune cells and mRNA expression levels in the ceRNA network.ResultsUltimately hsa-mir-425-3p, dual specificity phosphatase 1, and 24 lncRNAs were identified in the ceRNA network. The functional enrichment analyses showed that these lncRNAs, miRNAs, and mRNAs are involved in various significant biological process, such as the regulation of leukocyte migration, Mitogen-Activated Protein (MAP) kinase tyrosine/serine/threonine phosphatase activity, the interleukin-17 signaling pathway, the tumor necrosis factor signaling pathway, and osteoclast differentiation, and can also have a strong effect on immune cell infiltration.ConclusionsThe dual-specificity phosphatase 1-specific ceRNA network can be used as a diagnostic tool to assess the progression of OA patients.

Integrative computational approach identifies immune-relevant biomarkers in ulcerative colitis.

Ulcerative colitis is a common inflammatory bowel disease with a complex genetic and immune etiology. Immune infiltration plays a vital role in the development of ulcerative colitis. To explore potential biomarkers for ulcerative colitis and analyze characteristics of immune cell infiltration, we used bioinformatic analyses, including machine learning algorithms, cell type deconvolution methods, and pathway enrichment methods. In this study, we identified 216 differentially expressed mRNAs (DEMs), of which 153 were upregulated, and 63 were downregulated genes. DEMs were mainly enriched in infiltrating neutrophils and regulation of leukocyte migration. Moreover, eight candidate biomarkers, DPP10, MST1L, DPP10‐AS1, CEP55, ACSL1, MGP, OLFM4, and SGK1, were identified. Of these candidate biomarkers, MST1L, OLFM4, and DPP10 were then validated in the GSE48958 dataset and were predicted to be strongly correlated with infiltrating immune cells of ulcerative colitis. The underlying mechanism of these key genes in the development of colitis was also predicted by gene set variation analysis. To further validate these biomarkers' expression in ulcerative colitis, we determined mRNA levels of SGK1, CEP55, ACSL1, OLFM4, and DPP10 in lipopolysaccharides (LPS)‐stimulated Raw264.7 cells by quantitative reverse transcription‐polymerase chain reaction. We also examined SGK1, CEP55, ACSL1, OLFM4, DPP10, and MGP expression in the colon tissues of dextran sodium sulfate‐induced colitis mice. Consistent with the predicted computational results, the mRNA levels of these candidate genes were markedly changed in LPS‐stimulated Raw264.7 cells and inflamed colon tissues. Hence, our findings indicated that these critical genes may act as diagnostic biomarkers for ulcerative colitis and that differential immune infiltration cells may help illustrate the progression of ulcerative colitis.

CXCL12-stimulated lymphocytes produce secondary stimulants that affect the surrounding cell chemotaxis

Chemotactic factors locally secreted from tissues regulate leukocyte migration via cell membrane receptors that induce intracellular signals. It has been suggested that neutrophils stimulated by bacterial peptides secrete a secondary stimulant that enhances the chemotactic cell migration of the surrounding cells. This paracrine mechanism contributes to chemokine-dependent neutrophil migration, however, it has not yet been extensively studied in lymphocytes. In this study, we provide evidence that lymphocytes stimulated by the chemokine, CXCL12, affect the CXCR4-independent chemotactic response of the surrounding cells. We found that CXCR4-expressing lymphocytes or the conditioned medium from CXCL12-stimulated cells promoted CXCR4-deficient cell chemotaxis. In contrast, the conditioned medium from CXCL12-stimulated cells suppressed CCR7 ligand-dependent directionality and the cell migration speed of CXCR4-deficient cells. These results suggest that paracrine factors from CXCL12-stimulated cells navigate surrounding cells to CXCL12 by controlling the responsiveness to CCR7 ligand chemokines and CXCL12.

Glycosylation Regulates N-Terminal Proteolysis and Activity of the Chemokine CCL14.

Chemokines are secreted proteins that regulate leukocyte migration during inflammatory responses by signaling through chemokine receptors. Full length CC chemokine ligand 14, CCL14(1-74), is a weak agonist for the chemokine receptor CCR1, but its activity is substantially enhanced upon proteolytic cleavage to CCL14(9-74). CCL14 is O-glycosylated at Ser7, adjacent to the site of proteolytic activation. To determine whether glycosylation regulates the activity of CCL14, we used native chemical ligation to prepare four homogeneously glycosylated variants of CCL14(1-74). Each protein was assembled from three synthetic peptide fragments in "one-pot" using two sequential ligation reactions. We show that while glycosylation of CCL14(1-74) did not affect CCR1 binding affinity or potency of activation, sialylated variants of CCL14(1-74) exhibited reduced activity after treatment with plasmin compared to nonsialylated forms. These data indicate that glycosylation may influence the biological activity of CCL14 by regulating its conversion from the full-length to the truncated, activated form.

Elevated lymphocyte specific protein 1 expression is involved in the regulation of leukocyte migration and immunosuppressive microenvironment in glioblastoma.

Immune cell infiltration mediates therapeutic response to immune therapies. The investigation on the genes regulating leukocyte migration may help us to understand the mechanisms regulating immune cell infiltration in tumor microenvironment. Here, we collected the data from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) to analyze the expression of leukocyte migration related genes in glioblastoma (GBM). Lymphocyte specific protein 1 (LSP1) was identified as the only gene in this family which not only has an elevated expression, but also serve as an independent predictive factor for progressive malignancy in glioma. We further confirmed these results in clinical glioma samples by quantitative PCR, immunofluorescence, immunohistochemistry, and western blot. Moreover, LSP1 expression was closely related to the response to radio- and chemotherapy in GBM, and positively correlated with immunosuppressive cell populations, including M2 macrophages, neutrophil, and regulatory T cell. Additionally, elevated LSP-1 expression enhanced the expression of immunosuppression related genes like programmed cell death 1 (PD1) and leukocyte associated immunoglobulin like receptor 1 (LAIR1) in macrophages. LSP1 also promoted the migration of macrophages. Together, our study suggests a novel role of LSP1 contributing to immunosuppressive microenvironment in GBM and serving as a potential therapeutic target for it.

Integrated Bioinformatics Analysis of Master Regulators in Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and rapidly lethal tumors. However, limited advances have been made to prolong the survival and to reduce the mortality over the last decades. Therefore, identifying the master regulators underlying ATC progression is desperately needed. In our present study, three datasets including GSE33630, GSE29265, and GSE65144 were retrieved from Gene Expression Omnibus with a total of 32 ATC samples and 78 normal thyroid tissues. A total of 1804 consistently changed differentially expressed genes (DEGs) were identified from three datasets. KEGG pathways enrichment suggested that upregulated DEGs were mainly enriched in ECM-receptor interaction, cell cycle, PI3K-Akt signaling pathway, focal adhesion, and p53 signaling pathway. Furthermore, key gene modules in PPI network were identified by Cytoscape plugin MCODE and they were mainly associated with DNA replication, cell cycle process, collagen fibril organization, and regulation of leukocyte migration. Additionally, TOP2A, CDK1, CCNB1, VEGFA, BIRC5, MAPK1, CCNA2, MAD2L1, CDC20, and BUB1 were identified as hub genes of the PPI network. Interestingly, module analysis showed that 8 out of 10 hub genes participated in Module 1 network and more than 70% genes of Module 2 consisted of collagen family members. Notably, transcription factors (TFs) regulatory network analysis indicated that E2F7, FOXM1, and NFYB were master regulators of Module 1, while CREB3L1 was the master regulator of Module 2. Experimental validation showed that CREB3L1, E2F7, and FOXM1 were significantly upregulated in ATC tissue and cell line when compared with normal thyroid group. In conclusion, the TFs regulatory network provided a more detail molecular mechanism underlying ATC occurrence and progression. TFs including E2F7, FOXM1, CREB3L1, and NFYB were likely to be master regulators of ATC progression, suggesting their potential role as molecular therapeutic targets in ATC treatment.

Soluble TREM2 CSF concentration in Alzheimer’s disease track VCAM1, known to regulate leukocyte migration into the brain (P3.1-028)

Soluble TREM2 CSF concentration in Alzheimer’s disease track VCAM1, known to regulate leukocyte migration into the brain (P3.1-028)

Platelet glycoprotein VI and C-type lectin-like receptor 2 deficiency accelerates wound healing by impairing vascular integrity in mice.

Platelets promote wound healing by forming a vascular plug and by secreting growth factors and cytokines. Glycoprotein (GP)VI and C-type lectin-like receptor (CLEC)-2 signal through a (hem)-immunoreceptor tyrosine-based activation motif, which induces platelet activation. GPVI and CLEC-2 support vascular integrity during inflammation in the skin through regulation of leukocyte migration and function, and by sealing sites of vascular damage. In this study, we investigated the role of impaired vascular integrity due to GPVI and/or CLEC-2 deficiency in wound repair using a full-thickness excisional skin wound model in mice. Transgenic mice deficient in both GPVI and CLEC-2 exhibited accelerated skin wound healing, despite a marked impairment in vascular integrity. The local and temporal bleeding in the skin led to greater plasma protein entry, including fibrinogen and clotting factors, was associated with increased fibrin generation, reduction in wound neutrophils and M1 macrophages, decreased level of tumor necrosis factor (TNF)-α, and enhanced angiogenesis at day 3 after injury. Accelerated wound healing was not due to developmental defects in CLEC-2 and GPVI double-deficient mice as similar results were observed in GPVI-deficient mice treated with a podoplanin-blocking antibody. The rate of wound healing was not altered in mice deficient in either GPVI or CLEC-2. Our results show that, contrary to defects in coagulation, bleeding following a loss of vascular integrity caused by platelet CLEC-2 and GPVI deficiency facilitates wound repair by increasing fibrin(ogen) deposition, reducing inflammation, and promoting angiogenesis.

CXCL4 and CXCL4L1 in cancer

Chemokines regulate leukocyte migration during physiological and pathological conditions. It is currently accepted that these chemotactic cytokines are also important in the development and progression of cancer. CXCL4 and its non-allelic variant CXCL4L1 are two platelet-associated chemokines that have been attributed anti-tumoral activity as a result of their angiostatic potential and the chemotactic activity for anti-tumoral leukocytes. Here we review the role of CXCL4 and CXCL4L1 in cancer, the use of both chemokines as cancer biomarkers and discuss some possible therapeutic opportunities.