M1-type polarized macrophage contributes to brain damage through CXCR3.2/CXCL11 pathways after RGNNV infection in grouper.

The vertebrate central nervous system (CNS) is the most complex system of the body. The CNS, especially the brain, is generally regarded as immune-privileged. However, the specialized immune strategies in the brain and how immune cells, specifically macrophages in the brain, respond to virus invasion remain poorly understood. Therefore, this study aimed to examine the potential immune response of macrophages in the brain of orange-spotted groupers (Epinephelus coioides) following red-spotted grouper nervous necrosis virus (RGNNV) infection. We observed that RGNNV induced macrophages to produce an inflammatory response in the brain of orange-spotted grouper, and the macrophages exhibited M1-type polarization after RGNNV infection. In addition, we found RGNNV-induced macrophage M1 polarization via the CXCR3.2- CXCL11 pathway. Furthermore, we observed that RGNNV triggered M1 polarization in macrophages, resulting in substantial proinflammatory cytokine production and subsequent damage to brain tissue. These findings reveal a unique mechanism for brain macrophage polarization, emphasizing their role in contributing to nervous tissue damage following viral infection in the CNS.

Partial recovery of peripheral blood monocyte subsets in head and neck squamous cell carcinoma patients upon radio(chemo)therapy is associated with decreased plasma CXCL11.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) represents a common and heterogeneous malignancy of the oral cavity, pharynx and larynx. Surgery and radio(chemo)therapy are the standard treatment options and also have great influence on the composition of the tumor microenvironment and immune cell functions. However, the impact of radio(chemo)therapy on the distribution and characteristics of circulating monocyte subsets in HNSCC are not fully understood. METHODS: Expression patterns of adhesion molecules and chemokine receptors CD11a (integrin-α L; LFA-1), CD11b (integrin-α M; Mac-1), CD11c (integrin-α X), CX3CR1 (CX3CL1 receptor) and checkpoint molecule PD-L1 (programmed cell death ligand-1) were investigated upon radio(chemo)therapeutic treatment using flow cytometry. Furthermore, comprehensive analysis of plasma cytokines was performed before and after treatment using ELISA measurements. RESULTS: Our data reveal a partial recovery of circulating monocytes in HNSCC patients upon radio(chemo)therapeutic treatment, with differential effects of the individual therapy regimen. PD-L1 expression on non-classical monocytes significantly correlates with the individual plasma levels of chemokine CXCL11 (C-X-C motif chemokine 11). CONCLUSIONS: Further comprehensive investigations on larger patient cohorts are required to elucidate the meaningfulness of peripheral blood monocyte subsets and chemokine CXCL11 as potential bioliquid indicators in HNSCC with regard to therapy response and the individual immunological situation.

RSAD2 is abundant in atherosclerotic plaques and promotes interferon-induced CXCR3-chemokines in human smooth muscle cells.

In atherosclerotic lesions, monocyte-derived macrophages are major source of interferon gamma (IFN-γ), a pleotropic cytokine known to regulate the expression of numerous genes, including the antiviral gene RSAD2. While RSAD2 was reported to be expressed in endothelial cells of human carotid lesions, its significance for the development of atherosclerosis remains utterly unknown. Here, we harnessed publicly available human carotid atherosclerotic data to explore RSAD2 in lesions and employed siRNA-mediated gene-knockdown to investigate its function in IFN-γ-stimulated human aortic smooth muscle cells (hAoSMCs). Silencing RSAD2 in IFN-γ-stimulated hAoSMCs resulted in reduced expression and secretion of key CXCR3-chemokines, CXCL9, CXCL10, and CXCL11. Conditioned medium from RSAD2-deficient hAoSMCs exhibited diminished monocyte attraction in vitro compared to conditioned medium from control cells. Furthermore, RSAD2 transcript was elevated in carotid lesions where it was expressed by several different cell types, including endothelial cells, macrophages and smooth muscle cells. Interestingly, RSAD2 displayed significant correlations with CXCL10 (r = 0.45, p = 0.010) and CXCL11 (r = 0.53, p = 0.002) in human carotid lesions. Combining our findings, we uncover a novel role for RSAD2 in hAoSMCs, which could potentially contribute to monocyte recruitment in the context of atherosclerosis.

Therapeutic prime/pull vaccination of HSV-2-infected guinea pigs with the ribonucleotide reductase 2 (RR2) protein and CXCL11 chemokine boosts antiviral local tissue-resident and effector memory CD4+ and CD8+ T cells and protects against recurrent genital herpes.

Following acute herpes simplex virus type 2 (HSV-2) infection, the virus undergoes an asymptomatic latent infection of sensory neurons of dorsal root ganglia (DRG). Chemical and physical stress cause intermittent virus reactivation from latently infected DRG and recurrent virus shedding in the genital mucosal epithelium causing genital herpes in symptomatic patients. While T cells appear to play a role in controlling virus reactivation from DRG and reducing the severity of recurrent genital herpes, the mechanisms for recruiting these T cells into DRG and the vaginal mucosa (VM) remain to be fully elucidated. The present study investigates the effect of CXCL9, CXCL10, and CXCL11 T-cell-attracting chemokines on the frequency and function of DRG- and VM-resident CD4+ and CD8+ T cells and its effect on the frequency and severity of recurrent genital herpes in the recurrent herpes guinea pig model. HSV-2 latent-infected guinea pigs were immunized intramuscularly with the HSV-2 ribonucleotide reductase 2 (RR2) protein (Prime) and subsequently treated intravaginally with the neurotropic adeno-associated virus type 8 expressing CXCL9, CXCL10, or CXCL11 chemokines to recruit CD4+ and CD8+ T cells into the infected DRG and VM (Pull). Compared to the RR2 therapeutic vaccine alone, the RR2/CXCL11 prime/pull therapeutic vaccine significantly increased the frequencies of functional tissue-resident and effector memory CD4+ and CD8+ T cells in both DRG and VM tissues. This was associated with less virus in the healed genital mucosal epithelium and reduced frequency and severity of recurrent genital herpes. These findings confirm the role of local DRG- and VM-resident CD4+ and CD8+ T cells in reducing virus shedding at the vaginal site of infection and the severity of recurrent genital herpes and propose the novel prime-pull vaccine strategy to protect against recurrent genital herpes.IMPORTANCEThe present study investigates the novel prime/pull therapeutic vaccine strategy to protect against recurrent genital herpes using the latently infected guinea pig model. In this study, we used the strategy that involves immunization of herpes simplex virus type 2-infected guinea pigs using a recombinantly expressed herpes tegument protein-ribonucleotide reductase 2 (RR2; prime), followed by intravaginal treatment with the neurotropic adeno-associated virus type 8 expressing CXCL9, CXCL10, or CXCL11 T-cell-attracting chemokines to recruit T cells into the infected dorsal root ganglia (DRG) and vaginal mucosa (VM) (pull). We show that the RR2/CXCL11 prime-pull therapeutic vaccine strategy elicited a significant reduction in virus shedding in the vaginal mucosa and decreased the severity and frequency of recurrent genital herpes. This protection was associated with increased frequencies of functional tissue-resident (TRM cells) and effector (TEM cells) memory CD4+ and CD8+ T cells infiltrating latently infected DRG tissues and the healed regions of the vaginal mucosa. These findings shed light on the role of tissue-resident and effector memory CD4+ and CD8+ T cells in DRG tissues and the VM in protection against recurrent genital herpes and propose the prime-pull therapeutic vaccine strategy in combating genital herpes.

Diagnostic accuracy and cellular origin of pleural fluid CXCR3 ligands for tuberculous pleural effusion.

BACKGROUND: Pleural biomarkers represent potential diagnostic tools for tuberculous pleural effusion (TPE) due to their advantages of low cost, short turnaround time, and less invasiveness. This study evaluated the diagnostic accuracy of two CXCR3 ligands, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL11, for TPE. In addition, we investigated the cellular origins and biological roles of CXCL9 and CXCL11 in the development of TPE. METHODS: This double-blind study prospectively enrolled patients with undiagnosed pleural effusion from two centers (Hohhot and Changshu) in China. Pleural fluid on admission was obtained and levels of CXCL9 and CXCL11 were measured by an enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristic (ROC) curve and the decision curve analysis (DCA) were used to evaluate their diagnostic accuracy and net benefit, respectively. THP-1 cell-derived macrophages were treated with Bacillus Calmette-Guérin (BCG), and quantitative real-time PCR (qRT-PCR) and ELISA were used to determine the mRNA and protein levels of CXCL9 and CXCL11. The chemoattractant activities of CXCL9 and CXCL11 for T helper (Th) cells were analyzed by a transwell assay. RESULTS: One hundred and fifty-three (20 TPEs and 133 non-TPEs) patients were enrolled in the Hohhot Center, and 58 (13 TPEs and 45 non-TPEs) were enrolled in the Changshu Center. In both centers, we observed increased CXCL9 and CXCL11 in TPE patients. The areas under the ROC curves (AUCs) of pleural CXCL9 and CXCL11 in the Hohhot Center were 0.70 (95 % CI: 0.55-0.85) and 0.68 (95 % CI: 0.52-0.84), respectively. In the Changshu Center, the AUCs of CXCL9 and CXCL11 were 0.96 (95 % CI: 0.92-1.00) and 0.97 (95 % CI: 0.94-1.00), respectively. The AUCs of CXCL9 and CXCL11 decreased with the advancement of age. The decision curves of CXCL9 and CXCL11 showed net benefits in both centers. CXCL9 and CXCL11 were upregulated in BCG-treated macrophages. Pleural fluid from TPE and conditioned medium from BCG-treated macrophages were chemotactic for Th cells. Anti-CXCL9 or CXCL11 neutralizing antibodies could partly block the chemotactic activity. CONCLUSIONS: Pleural CXCL9 and CXCL11 are potential diagnostic markers for TPE, but their diagnostic accuracy is compromised in elderly patients. CXCL9 and CXCL11 can promote the migration of peripheral Th cells, thus representing a therapeutic target for the treatment of TPE.

The Role of CXCL11 and its Receptors in Cancer: Prospective but Challenging Clinical Targets.

Chemokine ligand 11 is a member of the CXC chemokine family and exerts its biological function mainly through binding to CXCR3 and CXCR7. The CXCL11 gene is ubiquitously overexpressed in various human malignant tumors; however, its specific mechanisms vary among different cancer types. Recent studies have found that CXCL11 is involved in the activation of multiple oncogenic signaling pathways and is closely related to tumorigenesis, progression, chemotherapy tolerance, immunotherapy efficacy, and poor prognosis. Depending on the specific expression of its receptor subtype, CXCL11 also has a complex 2-fold role in tumours; therefore, directly targeting the structure-function of CXCL11 and its receptors may be a challenging task. In this review, we summarize the biological functions of CXCL11 and its receptors and their roles in various types of malignant tumors and point out the directions for clinical applications.

CXCL11 is found in many types of cancer and affects how cancer cells grow and respond to treatments. This paper delves into the intricate dance between CXCL11 and its receptors in various types of cancer. Like a versatile actor playing different roles on stage, CXCL11 can either promote or hinder cancer growth depending on its interaction with specific receptors. Understanding how CXCL11 works could help develop new treatments for cancer, but it's a complex challenge because CXCL11 can have different effects depending on the type of cancer and which receptors it binds to.

Antiviral treatment significantly reduces the levels of CXCL9, CXCL10 and CXCL11 in chronic hepatitis C.

In this study, we aimed to elucidate the changes in the immune response during antiviral treatment of patients with chronic hepatitis C, with an emphasis on the chemokine dynamics and their association with liver fibrosis. Serum concentrations of 12 chemokines. (CCL2, CCL3, CCL4, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL8, CXCL9, CXCL10 and CXCL11) were measured in 32 patients with chronic hepatitis C before direct-acting antiviral treatment and after sustained virological response using bead-based flow cytometry. Chemokine levels were also measured in 14 sex- and age-matched healthy individuals. Concentrations of CXCL9, CXCL10, CXCL11 and CCL20 were significantly higher in chronic hepatitis C patients before direct-acting antiviral treatment compared to healthy individuals. We also observed a significant reduction in CXCL9, CXCL10 and CXCL11 levels after sustained virological response. Furthermore, we demonstrated a strong positive correlation between CXCL9, CXCL10 and CXCL11 levels before antiviral treatment. When considering liver fibrosis, we found significantly higher levels of CXCL10 and lower levels of CCL17 and CXCL5 in pre-treatment patients with severe fibrosis. None of the analysed chemokines were able to predict METAVIR fibrosis score reduction after sustained virological response. The results of this study emphasize the importance of proinflammatory pathways in liver fibrosis immunopathology during chronic hepatitis C. Finally, our results also characterized CXCL10 as the chemokine which most accurately distinguished pre-treatment CHC patients and healthy individuals.

Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3.

Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this ß-arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC50 = 8.3) to human ACKR3, as measured in [125I]CXCL12 competition binding experiments. Moreover, in a bioluminescence resonance energy transfer-based ß-arrestin2 recruitment assay VUF15485 acts as a potent ACKR3 agonist (pEC50 = 7.6) and shows a similar extent of receptor activation compared with CXCL12 when using a newly developed, fluorescence resonance energy transfer-based ACKR3 conformational sensor. Moreover, the ACKR3 agonist VUF15485, tested against a (atypical) chemokine receptor panel (agonist and antagonist mode), proves to be selective for ACKR3. VUF15485 labeled with tritium at one of its methoxy groups ([3H]VUF15485), binds ACKR3 saturably and with high affinity (K d = 8.2 nM). Additionally, [3H]VUF15485 shows rapid binding kinetics and consequently a short residence time (<2 minutes) for binding to ACKR3. The selectivity of [3H]VUF15485 for ACKR3, was confirmed by binding studies, whereupon CXCR3, CXCR4, and ACKR3 small-molecule ligands were competed for binding against the radiolabeled agonist. Interestingly, the chemokine ligands CXCL11 and CXCL12 are not able to displace the binding of [3H]VUF15485 to ACKR3. The radiolabeled VUF15485 was subsequently used to evaluate its binding pocket. Site-directed mutagenesis and docking studies using a recently solved cryo-EM structure propose that VUF15485 binds in the major and the minor binding pocket of ACKR3. SIGNIFICANCE STATEMENT: The atypical chemokine receptor atypical chemokine receptor 3 (ACKR3) is considered an interesting drug target in relation to cancer and multiple sclerosis. The study reports on new chemical biology tools for ACKR3, i.e., a new agonist that can also be radiolabeled and a new ACKR3 conformational sensor, that both can be used to directly study the interaction of ACKR3 ligands with the G protein-coupled receptor.

Molecular cloning, characterization and expression analysis of the Chinese soft-shelled turtle (Pelodiscus sinensis) chemokine CXCL11.

Chemokines are small, secreted proteins with chemoattractive properties, which play an important role in the recruitment and activation of immune cells. CXCL11 is a CXC chemokine specific for the CXCR3 receptors, which has been shown to mediate the generation of Th1-type immune responses and have bactericidal effects similar to defensins. Herein, we cloned the full-length cDNA of Chinese soft-shelled turtle (Pelodiscus sinensis) CXCL11, designated as PsCXCL11, which consist of an open reading frame (ORF) of 282 bp encoding 93 amino acids, with estimated molecular weight of 10.055 kDa and isoelectric point of 10.37. The deduced PsCXCL11 sequence had a signal peptide, a highly conserved family-specific small cytokine (SCY) domain, one putative N-glycosylation site and ten potential phosphorylation sites. Phylogenetic analysis showed a close relationship between P. sinensis and Chelydra Serpentina CXCL11. P. sinensis CXCL11 basal expression levels were higher in heart, kidney and spleen than in other organs of health turtles. Infections of Aeromonas hydrophila and Staphylococcus aureus led to significant upregulation of P. sinensis CXCL11 in the blood, while significant upregulation of PsCXCL11 were observed in liver and spleen after infection of A. hydrophila, but not S. aureus. PsCXCL11 recombinant protein with His-tag was successfully expressed by an auto-inducible expression system, and purified by Ni-NTA affinity chromatography. These findings laid a solid foundation for further research towards development of the Chinese soft-shelled turtle as a model for the role of CXCL11 in regulating inflammatory responses to stimulation by invading pathogens.

A multi-epitope/CXCL11 prime/pull coronavirus mucosal vaccine boosts the frequency and the function of lung-resident memory CD4+ and CD8+ T cells and enhanced protection against COVID-19-like symptoms and death caused by SARS-CoV-2 infection.

IMPORTANCE: Although the current rate of SARS-CoV-2 infections has decreased significantly, COVID-19 still ranks very high as a cause of death worldwide. As of October 2023, the weekly mortality rate is still at 600 deaths in the United States alone, which surpasses even the worst mortality rates recorded for influenza. Thus, the long-term outlook of COVID-19 is still a serious concern outlining the need for the next-generation vaccine. This study found that a prime/pull coronavirus vaccine strategy increased the frequency of functional SARS-CoV-2-specific CD4+ and CD8+ memory T cells in the lungs of SARS-CoV-2-infected triple transgenic HLA-DR*0101/HLA-A*0201/hACE2 mouse model, thereby resulting in low viral titer and reduced COVID-19-like symptoms.

lncRNA CLRN1-AS1 reduces adhesion ability of human trophoblasts via CXCL10/CXCL11.

INTRODUCTION: Trophoblast cells play an important role in embryo recognition and localization, as well as placental development during embryo implantation. Dysfunction of trophoblastic cells causes pathological changes that lead to insufficient recognition, positioning, and adhesion during embryo implantation, ultimately leading to embryo development has stopped. METHODS: High-throughput sequencing was used to identify differentially expressed the mRNA and lncRNA in the villi tissue of pregnant women diagnosed with embryo cessation. In vitro implantation cell models, characteristic analysis, and bio information analysis confirmed that CLRN1-AS1 affected the adhesion function of trophoblast cells by influencing the chemokines CXCL10/CXCL11. RESULTS: High throughput sequencing technology was used to identify 438 differentially expressed mRNAs and 41 lncRNAs. The three lncRNAs, namely CLRN1-AS1, USP27X-AS1, and AC104809.4, were screened by the mRNA-lncRNA network. In vitro implantation model suggested that all three lncRNAs could affect the adhesion between trophoblast cells, among which CLRN1-AS1 had the most significant effect. Characteristic analysis and correlation analysis showed that CLRN1-AS1 was closely related to the expression of six adhesion-related genes, LAMA1, FGL2, ITGB2, FBN1, EMP2, and PODN. Cell experiments and re-sequencing confirmed that CLRN1-AS1 could affect the adhesion ability of trophoblast cells to the extracellular matrix, and its process was related to the chemokine CXCL10/CXCL11. DISCUSSION: These results constructed the network of mRNA-lncRNA and enrichment when embryonic development has stopped and found CLRN1-AS1 highly correlated to failure of embryo implantation, and revealed that CLRN1-AS1 modulates the adhesion ability of trophoblast cells to the extracellular matrix via the chemokines CXCL10/CXCL11 during the early stage of embryo implantation.

Reassessing the adrenomedullin scavenging function of ACKR3 in lymphatic endothelial cells.

Atypical chemokine receptor 3 (ACKR3) is a scavenger of the chemokines CXCL11 and CXCL12 and of several opioid peptides. Additional evidence indicates that ACKR3 binds two other non-chemokine ligands, namely the peptide hormone adrenomedullin (AM) and derivatives of the proadrenomedullin N-terminal 20 peptide (PAMP). AM exhibits multiple functions in the cardiovascular system and is essential for embryonic lymphangiogenesis in mice. Interestingly, AM-overexpressing and ACKR3-deficient mouse embryos both display lymphatic hyperplasia. Moreover, in vitro evidence suggested that lymphatic endothelial cells (LECs), which express ACKR3, scavenge AM and thereby reduce AM-induced lymphangiogenic responses. Together, these observations have led to the conclusion that ACKR3-mediated AM scavenging by LECs serves to prevent overshooting AM-induced lymphangiogenesis and lymphatic hyperplasia. Here, we further investigated AM scavenging by ACKR3 in HEK293 cells and in human primary dermal LECs obtained from three different sources in vitro. LECs efficiently bound and scavenged fluorescent CXCL12 or a CXCL11/12 chimeric chemokine in an ACKR3-dependent manner. Conversely, addition of AM induced LEC proliferation but AM internalization was found to be independent of ACKR3. Similarly, ectopic expression of ACKR3 in HEK293 cells did not result in AM internalization, but the latter was avidly induced upon co-transfecting HEK293 cells with the canonical AM receptors, consisting of calcitonin receptor-like receptor (CALCRL) and receptor activity-modifying protein (RAMP)2 or RAMP3. Together, these findings indicate that ACKR3-dependent scavenging of AM by human LECs does not occur at ligand concentrations sufficient to trigger AM-induced responses mediated by canonical AM receptors.

The Serum Level of CXCL9, CXCL10, and CXCL11 and the Expression of CXCR3 of Peripheral Blood Mononuclear Cells in Brucellosis Patients.

Brucella spp. can replicate in human endothelial cells, inducing an inflammatory response with increased expression of chemokines. Although Brucella infects humans, its ability to induce the production of chemokines by lung cells is unknown. Therefore, the current investigation was designed to examine the association between brucellosis and CXCL9, 10, and 11 chemokines. The patient group included 71 patients suffering from Brucella infection and the control group consisted of 50 healthy ranchers from the same geographical area. Serum levels of CXCL9, CXCL10, and CXCL11 were analyzed by ELISA. The fold changes of CXCR3 expression against ß-actin were determined by real-time-PCR technique. Western blotting analysis was also applied for evaluating the expression of CXCR3 at protein level. The results of this study showed that the serum levels of CXCL9, CXCL10, and CXCL11 are significantly increased in acute brucellosis patients in comparison to control as indicated by ELISA test, mRNA levels of CXCR3 by Real-time PCR as well as protein levels of CXCR3 by Western blot analysis. According to findings, these chemokines have the potential to serve as markers for brucellosis patients. Taken together, cytokine/chemokine network was active in acute brucellosis patients, and it is suggested to evaluate other cytokines in future studies.

Differential Anti-Tumor Effects of IFN-Inducible Chemokines CXCL9, CXCL10, and CXCL11 on a Mouse Squamous Cell Carcinoma Cell Line.

Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the differential anti-tumor effects of IFN-inducible chemokines are not completely understood. In this study, we investigated the anti-tumor effects of IFN-inducible chemokines by transferring chemokine expression vectors into a mouse squamous cell carcinoma cell line, SCCVII, to generate a cell line stably expressing chemokines and transplanted it into nude mice. The results showed that CXCL9- and CXCL11-expressing cells markedly inhibited tumor growth, whereas CXCL10-expressing cells did not inhibit growth. The NH2-terminal amino acid sequence of mouse CXCL10 contains a cleavage sequence by dipeptidyl peptidase 4 (DPP4), an enzyme that cleaves the peptide chain of chemokines. IHC staining indicated DPP4 expression in the stromal tissue, suggesting CXCL10 inactivation. These results suggest that the anti-tumor effects of IFN-inducible chemokines are affected by the expression of chemokine-cleaving enzymes in tumor tissues.

Stem-like signatures in human meningioma cells are under the control of CXCL11/CXCL12 chemokine activity.

BACKGROUND: Meningiomas are mainly benign brain tumors, although about 20% of histologically benign cases are clinically aggressive and recur after resection. We hypothesize that meningioma brain invasiveness and recurrence may be related to the presence of cancer stem cells and their high responsiveness to the CXCL12-CXCR4/CXCR7 chemokine axis. The aim of this study was to isolate meningioma stem cells from human samples, characterize them for biological features related to malignant behavior, and to identify the role of CXCR4/CXCR7 in these processes. METHODS: Meningioma stem cells were isolated from patient-derived primary cultures in stem cell-permissive conditions, and characterized for phenotype, self-renewal, proliferation and migration rates, vasculogenic mimicry (VM), and in vivo tumorigenesis, in comparison with differentiated meningioma cells and stem-like cells isolated from normal meninges. These cell populations were challenged with CXCL12 and CXCL11 and receptor antagonists to define the chemokine role in stem cell-related functions. RESULTS: Stem-like cells isolated from meningioma cultures display higher proliferation and migration rates, and VM, as compared to meningioma non-stem cells or cells isolated from normal meninges and were the only tumorigenic population in vivo. In meningioma cells, these stem-like functions were under the control of the CXCR4/CXCR7 chemokine axis. CONCLUSIONS: We report a role for CXCL11 and CXCL12 in the control of malignant features in stem-like cells isolated from human meningioma, providing a possible basis for the aggressive clinical behavior observed in subsets of these tumors. CXCR4/CXCR7 antagonists might represent a useful approach for meningioma at high risk of recurrence and malignant progression.

Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms.

Accumulation of T lymphocytes and neutrophils shows inversed association with the prognosis of cancer patients, suggesting infiltration of neutrophils and T cells might be differently regulated in tumor tissue. In this study, we stimulated neutrophils with PMA or LPS to produce neutrophil extracellular traps (NETs) and examined the effects on chemotactic migration of activated T cells to a representative T cell chemokine, CXCL11. Migration of the activated T cells was totally abrogated by PMA-stimulated neutrophils placed either in upper or lower chamber, which was mostly canceled by pretreatment with Catalase. Although LPS-stimulated neutrophils also inhibited T cell migration, depletion of NETs by ultracentrifugation or degradation of NETs with DNAse I restored T cell migration. Western blots showed that LPS-stimulated neutrophils thoroughly degraded CXCL11 with NETs dependent manner. Activated neutrophils inhibit T cell chemotaxis via multiple mechanisms including the release of H2O2 and chemokine degradation by NETs, which may suppress adaptive immunity.

Oxaliplatin inhibits colorectal cancer progression by inhibiting CXCL11 secreted by cancer-associated fibroblasts and the CXCR3/PI3K/AKT pathway

Purpose Colorectal cancer (CRC) is a malignant tumor. Oxaliplatin (OXA) can inhibit cancer-associated fibroblasts (CAFs)-induced cancer progression. This study sought to explore the mechanism of OXA in CAFs-induced CRC development. Methods CRC cell lines (Caco-2, SW620), normal fibroblasts (NFs), and CAFs were treated with OXA. NFs and CAFs were cultured. CAFs were treated with/without OXA (0.4 mM), and the supernatant was extracted as the conditioned medium (CM) to culture CRC cells. Cell malignant episodes, E-cadherin and Vimentin levels, CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 mRNA levels, CXCL11 protein level, and extracellular release were assessed. CAFs were transfected with interfering RNA sh-CXCL11 to silence CXCL11 or transfected with CXCL11 overexpression plasmids and treated with OXA to explore the role of CXCL11 in OXA-mediated CRC cells through CAFs. CXCL11 receptor CXCR3 levels in CRC cells and the PI3K/AKT pathway changes were examined. The xenogeneic tumor was transplanted in nude mice. CXCL11 and CXCR3 levels in tumor tissues, tumor volume, shape, size, weight, and Ki67 positive expressions were assessed. Results CRC cell growths and epithelial–mesenchymal transformation were stimulated after culture with CAFs–CM, while OXA averted these trends. CXCL11 mRNA level was elevated most significantly, and its protein and extracellular secretion levels were raised, while OXA diminished the levels. CXCL11 silencing weakened the effects of CAFs–CM on promoting CRC proliferation and malignant episodes and CXCL11 overexpression averted OXA property on inhibiting CAFs-promoted CRC cell growth (AU)

CXCL11 negatively regulated by MED19 favours antitumour immune infiltration in breast cancer.

BACKGROUND: Through microarray results, we found that the C-X-C motif chemokine ligand 11 (CXCL11) was negatively regulated by mediator complex subunit 19 (MED19), a protumour factor. However, the biological role and potential mechanism of CXCL11 need to be explored in breast cancer (BRCA). METHODS: The BRCA dataset was obtained from the Cancer Genome Atlas (TCGA) dataset. Our microarray data and the BRCA dataset of TCGA were analysed and visualized using the R software package. The mRNA and protein levels were measured by qRT-PCR and western blotting. RESULTS: Inhibition of MED19 in MDA-MB-231 cells caused CXCL11 upregulation. The relative positive regulation of cytokine pathways was enriched after MED19 knockdown. High CXCL11 was determined to be positively correlated with immune response activation, increased antitumour immune cell infiltration, immune checkpoint molecule expression, and enhanced sensitivity to immunotherapy and chemotherapy. Collectively, CXCL11 promoted antitumour immunity and was regulated by MED19 in BRCA. Clarifying the prognostic value and underlying mechanism of CXCL11 in BRCA could provide a theoretical basis to find new diagnostic and therapeutic targets.

Oxaliplatin inhibits colorectal cancer progression by inhibiting CXCL11 secreted by cancer-associated fibroblasts and the CXCR3/PI3K/AKT pathway.

PURPOSE: Colorectal cancer (CRC) is a malignant tumor. Oxaliplatin (OXA) can inhibit cancer-associated fibroblasts (CAFs)-induced cancer progression. This study sought to explore the mechanism of OXA in CAFs-induced CRC development. METHODS: CRC cell lines (Caco-2, SW620), normal fibroblasts (NFs), and CAFs were treated with OXA. NFs and CAFs were cultured. CAFs were treated with/without OXA (0.4 mM), and the supernatant was extracted as the conditioned medium (CM) to culture CRC cells. Cell malignant episodes, E-cadherin and Vimentin levels, CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 mRNA levels, CXCL11 protein level, and extracellular release were assessed. CAFs were transfected with interfering RNA sh-CXCL11 to silence CXCL11 or transfected with CXCL11 overexpression plasmids and treated with OXA to explore the role of CXCL11 in OXA-mediated CRC cells through CAFs. CXCL11 receptor CXCR3 levels in CRC cells and the PI3K/AKT pathway changes were examined. The xenogeneic tumor was transplanted in nude mice. CXCL11 and CXCR3 levels in tumor tissues, tumor volume, shape, size, weight, and Ki67 positive expressions were assessed. RESULTS: CRC cell growths and epithelial-mesenchymal transformation were stimulated after culture with CAFs-CM, while OXA averted these trends. CXCL11 mRNA level was elevated most significantly, and its protein and extracellular secretion levels were raised, while OXA diminished the levels. CXCL11 silencing weakened the effects of CAFs-CM on promoting CRC proliferation and malignant episodes and CXCL11 overexpression averted OXA property on inhibiting CAFs-promoted CRC cell growth. CXCR3 and PI3K and AKT1 phosphorylation levels were raised in the CAFs-CM group but diminished by OXA. CXCL11 overexpression in CAFs averted OXA property on inhibiting CAFs-activated CXCR3/PI3K/AKT in CRC cells. OXA also inhibited the progression of xenograft tumors by limiting CAFs-secreted CXCL11. CONCLUSIONS: OXA repressed CRC progression by inhibiting CAFs-secreted CXCL11 and the CXCR3/PI3K/AKT pathway.

CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.