Expression and regulation of the CXCL9-11 chemokines and CXCR3 receptor in Atlantic salmon (Salmo salar).

Chemokines are cytokines that mediate leukocyte traffic between the lymphoid organs, the bloodstream, and the site of tissue damage, which is essential for an efficient immune response. In particular, the gamma interferon (IFN- γ) inducible chemokines CXCL9, CXCL10, and CXCL11, and their receptor CXCR3, are involved in T cell and macrophage recruitment to the site of infection. The nature and function of these chemokines and their receptor are well-known in mammals, but further research is needed to achieve a similar level of understanding in fish immunity. Thus, in this study, we seek to identify the genes encoding the components of the Atlantic salmon (Salmo salar) CXCL9, CXCL10, CXCL11/CXCR3 axis (CXCL9-11/CXCR3), predict the protein structure from the amino acid sequence, and explore the regulation of gene expression as well as the response of these chemokines and their receptor to viral infections. The cxcl9, cxcl10, cxcl11, and cxcr3 gene sequences were retrieved from the databases, and the phylogenetic analysis was conducted to determine the evolutionary relationships. The study revealed an interesting pattern of clustering and conservation among fish and mammalian species. The salmon chemokine sequences clustered with orthologs from other fish species, while the mammalian sequences formed separate clades. This indicates a divergent evolution of chemokines between mammals and fish, possibly due to different evolutionary pressures. While the structural analysis of the chemokines and the CXCR3 receptor showed the conservation of critical motifs and domains, suggesting preserved functions and stability throughout evolution. Regarding the regulation of gene expression, some components of the CXCL9-11/CXCR3 axis are induced by recombinant gamma interferon (rIFN-γ) and by Infectious pancreatic necrosis virus (IPNV) infection in Atlantic salmon cells. Further studies are needed to explore the role of Atlantic salmon CXCL9-11 chemokines in regulating immune cell migration and endothelial activation, as seen in mammals. To the best of our knowledge, there have been no functional studies of chemokines to understand these effects in Atlantic salmon.

Clinical significance of serum CXCL9, CXCL10, and CXCL11 in patients with lupus nephritis.

STUDY DESIGN: Lupus nephritis (LN) is an autoimmune disease as a complication of systemic lupus erythematosus (SLE). LN is typically diagnosed through a combination of clinical evaluation as index scoring, and kidney biopsy as a more accurate but invasive examination. In the current study, we assessed serological markers including IFN-γ-inducible chemokines C-X-C motif chemokine ligand (CXCL)9, CXCL10, and CXCL11 in diagnosing LN. METHODS: A retrospective analysis was conducted on 160 SLE patients with and without LN. Fasting venous blood was collected from the study subjects for measuring serum levels of CXCL9, CXCL10, and CXCL11. The assessment of clinical disease activity in SLE was conducted using the SLE Disease Activity Index (SLEDAI)-2000 scoring system. LN disease activity was conducted using the Austin scoring system. LN was further confirmed following kidney biopsy, and data were compared by receiver operating characteristic (ROC) analysis. RESULTS: SLE patients with LN showed longer SLE duration, enhanced SLEDAI scores, lower serum anti-ds-DNA antibody levels when compared to SLE patients without LN. Specifically, these patients had significantly higher serum levels of CXCL9, CXCL10 and CXCL11. CXCL9, CXCL10, and CXCL11 showed positive correlation with SLE disease activity in SLE patients with LN. ROC analysis of CXCL9, CXCL10, and CXCL11 showed substantial enhancement of sensitivity and specificity for the diagnosis of LN in the patients with SLE. CONCLUSIONS: Serum CXCL9, CXCL10, and CXCL11 levels may improve the sensitivity and specificity for the diagnosis of LN in SLE patients.

Associations between Microglia and Astrocytic Proteins and Tau Biomarkers across the Continuum of Alzheimer's Disease.

Recent investigations implicate neuroinflammatory changes, including astrocyte and microglia activation, as crucial in the progression of Alzheimer's disease (AD) Thus, we compared selected proteins reflecting neuroinflammatory processes to establish their connection to AD pathologies. Our study, encompassing 80 subjects with (n = 42) AD, (n = 18) mild cognitive impairment (MCI) and (n = 20) non-demented controls compares the clinical potential of tested molecules. Using antibody-based methods, we assessed concentrations of NGAL, CXCL-11, sTREM1, and sTREM2 in cerebrospinal fluid (CSF). Proinflammatory proteins, NGAL, and CXCL-11 reached a peak in the early stage of the disease and allowed for the identification of patients with MCI. Furthermore, the concentration of the anti-inflammatory molecule sTREM2 was highest in the more advanced stage of the disease and permitted differentiation between AD and non-demented controls. Additionally, sTREM2 was biochemically linked to tau and pTau in the AD group. Notably, NGAL demonstrated superior diagnostic performance compared to classical AD biomarkers in discriminating MCI patients from controls. These findings suggest that proteins secreted mainly through microglia dysfunction might play not only a detrimental but also a protective role in the development of AD pathology.

[Clinicopathological characteristics of the CD8+ T lymphocytes infiltration and its mechanism in distinct molecular subtype of medulloblastoma].

OBJECTIVE: To investigate the characteristics of the CD8+ T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8+ T cells infiltration and prognosis, to study the function of C-X-C motif chemokine ligand 11 (CXCL11) and its receptor in CD8+ T cells infiltration into tumors and to explore the potential mechanism, and to provide the necessary clinicopathological basis for exploring the immunotherapy of MB. METHODS: In the study, 48 clinical MB samples (12 cases in each of 4 subtypes) were selected from the multiple medical center from 2012 to 2019. The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString PanCancer IO360TM Panel (NanoString Technologies). Immunohistochemistry (IHC) staining of formalin-fixed, paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8+ T cells in the MB four subtypes. Through bioinformatics analysis, the relationship between CD8+T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated. The expression of CXCR3 receptor on the surface of CD8+T cells in MB was verified by double immunofluorescence staining, and the underlying molecular mechanism of CD8+T cells infiltration into the tumor was explored. RESULTS: The characteristic index of CD8+T cells in the WNT subtype of MB was relatively high, suggesting that the number of CD8+T cells in the WNT subtype was significantly higher than that in the other three subtypes, which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus (GEO) database analysis by using R2 online data analysis platform. And the increase of CD8+T cells infiltration was positively correlated with the patient survival. The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes. Immunofluorescence staining showed the presence of CXCL11 receptor, CXCR3, on the surface of CD8+T cells, suggesting that the CD8+T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3. CONCLUSION: The CD8+T cells infiltrate more in the WNT subtype MB than other subtypes. The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system, and the patients with more infiltration of CD8+T cells in tumor have better prognosis. This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8+T cells infiltration in MB, and give a new potential therapeutic target for the future immunotherapy of MB.

ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects.

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases.

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.

HIF-1α Mediates Immunosuppression and Chemoresistance in Colorectal Cancer by Inhibiting CXCL9, -10 and -11.

Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression resulted in increased or decreased CXCL9, -10, and -11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, -10, and -11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, -10, and -11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, -10 and -11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity.

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.

CD4+ T cell-derived IFN-γ and LIGHT synergistically upregulate chemokine production from airway smooth muscle cells.

Airway smooth muscle (ASM) remodeling in asthmatic airways may contribute to persistent airflow limitation and airway hyperresponsiveness. CD4+ T cells infiltrate the ASM layer where they may induce a proliferative and secretory ASM cell phenotype. We studied the interaction between activated CD4+ T cells and ASM cells in co-culture in vitro and investigated the effects of CD4+ T cells on chemokine production by ASM cells. CD4+ T cells induced marked upregulation of C-X-C motif chemokine ligands (CXCL) 9, 10, and 11 in ASM cells. Blockade of the IFN-γ receptor on ASM cells prevented this upregulation. Furthermore, T cell-derived IFN-γ and LIGHT (lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) synergize in a dose-dependent manner to coordinately enhance CXCL9, 10, and 11 expression. The synergistic property of LIGHT was mediated exclusively through the lymphotoxin-ß receptor (LTBR), but not herpes virus entry mediator (HVEM). Disruption of LTBR signaling in ASM cells reduced CXCL9, 10, and 11 production and ASM cell-mediated CD4+ T cell chemotaxis. We conclude that the LIGHT-LTBR signaling axis acts together with IFN-γ to regulate chemokines that mediate lymphocyte infiltration in asthmatics.

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.

The Effect of Transplantation of Cultured Autologous Melanocytes on CXCL9, CXCL10 and CXCL11 Expressions in Vitiligo.

Background: Vitiligo is an acquired chronic autoimmune skin disorder with an estimated prevalence of 1% worldwide. The CD8+ T-cell-mediated chemokines such as CXCR3, CXCL9 and CXCL10 are the non-specific action immunomodulators that are responsible for the depigmentation and progression in vitiligo. Aim: This study aimed to explore the expression levels of serum CXCL9-11 in vitiligo patients who received the transplantation of cultured autologous melanocytes (TCAMs) before and after the operation and correlate their expressions with clinical stage, subtype and course of the vitiligo disease. Materials and Methods: The expression levels of serum CXCL9-11 were measured in the peripheral blood of 26 progressive vitiligo patients, 24 stable vitiligo, 13 TCAM patients and 30 healthy control (HC) cases using enzyme-linked immunosorbent assay (ELISA). The potential correlations between their expressions and disease features such as stage, type and surgical treatment were evaluated using Student's t-test. Results: The expression levels of serum CXCL9-11 increased by ~1.4, ~1.6 and ~2.3-fold in vitiligo patients compared with HCs (P < 0.01). The expression levels of all chemokines were significantly higher in progressive vitiligo patients than in stable vitiligo (P < 0.01). The increasing expression levels of serum CXCL9, CXCL10 and CXCL11 were significantly related to the different types of vitiligo patients (P < 0.05). Preoperative expression levels of serum CXCL9-11 were significantly higher than the post-operative expression levels (P < 0.01). Conclusion: Our results demonstrate that increasing expression levels of the CXC family play a key role in the immunopathogenesis of vitiligo. The abnormal expression of the CXC family may be considered an effective and therapeutic target for TCAM treatment.

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.

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.

Immunohistochemical Expression of Chemokine Receptor CXCR3 and its Ligand CXCL 11 in Basal Cell Carcinoma.

Introduction: Basal cell carcinoma (BCC) is the most common type of skin cancer worldwide. The pathogenesis of BCC involves interplay between various environmental and genetic factors. It is believed that chemokines play a significant role in the modulation of cancer growth by generating autocrine and paracrine signaling effects. The present study was conducted to elucidate the expression of chemokine, CXCL11, and its receptor CXCR3, and their interaction with tumor cells and peri-tumoral stroma in various subtypes of BCC. Aim and Objectives: The aim of this study was to evaluate the immunohistochemical expression of chemokine CXCL11 and its receptor CXCR3 in various subtypes of BCC. Materials and Methods: The study included 40 cases of histopathologically confirmed BCC. Clinical and histopathological features of various tumor subtypes were noted. Immunohistochemistry was performed using antibodies against CXCL11 and CXCR3, and these were assigned scores 0, 1, and 2 on the basis of immunohistochemical expression. Results: The median age of study participants was 65.0 ± 12.2 years with a male-to-female ratio of 1.5:1. The most common site was face, followed by neck, scalp, and back. The tumor subtypes included in the study were nodular (n = 20), pigmented (n = 8), infiltrating (n = 5), superficial (n = 4), and adenoid (n = 3). On immunohistochemistry, CXCR3 expression was seen in 34 (85%) cases with stromal inflammatory cells immunopositivity in 29 (72.5%) cases and tumor cells immunopositivity in 5 (12.5%) cases. CXCL11 expression was seen in 36 (90%) cases with weak expression in stroma and tumor in 18 cases and strong expression in the rest 18 cases. In individual subtypes, higher immunopositivity for CXCR3 and CXCL11 in tumor cells and peri-tumoral stroma was seen for nodular, infiltrating, and pigmented subtypes, compared to adenoid and superficial subtypes. Conclusion: Our study shows the enhanced expression of chemokine CXCL11 and its receptor CXCR3 in tumor cells and peri-tumoral stroma of BCC. This expression is greater in tumor cells of aggressive subtypes, i.e. nodular, infiltrating, and pigmented types. This suggests that receptor ligand pathway involving CXCR3 and CXCL11 plays a key role in pathogenesis of BCC, and blocking this pathway may result in inhibition of tumor growth. Thus, these chemokines may serve as future potential targets in developing novel therapeutic regimens against BCC.

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.

Chemokines in thyroid autoimmunity.

The chemokine receptor CXCR3 and its chemokines CXCL9, CXCL10, and CXCL11 are involved in the pathogenesis of autoimmune diseases. Th1 lymphocytes are recruited by Th1 chemokines, secreted by damaged cells. In inflamed tissues, the attracted Th1 lymphocytes induce the IFN-gamma and TNF-alpha release, that stimulates the secretion of Th1 chemokines, initiating and reiterating an amplification feedback loop. Autoimmune thyroid disorders (AITD) are the most recurrent autoimmune diseases, including Graves' disease (GD) and autoimmune thyroiditis, clinically defined by thyrotoxicosis and hypothyroidism, respectively. Graves' ophthalmopathy is one of GD extrathyroidal manifestations, occurring in ~30-50% of GD patients. In the early phase of AITD, the Th1 immune response is prevalent, and a following switch to a Th2 immune response has been shown in the late, inactive, phase. The reviewed data underline the importance of chemokines in thyroid autoimmunity and suggest CXCR3-receptor and its chemokines as potential targets of novel drugs for these disorders.

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)

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.

Perinatal mood and anxiety disorders: biomarker discovery using plasma proteomics.

BACKGROUND: Perinatal mood and anxiety disorders encompass a range of mental health disorders that occur during pregnancy and up to 1 year postpartum, affecting approximately 20% of women. Traditional risk factors, such as a history of depression and pregnancy complications including preeclampsia, are known. Their predictive utility, however, is not specific or sensitive enough to inform clinical decision-making or prevention strategies for perinatal mood and anxiety disorders. Better diagnostic and prognostic models are needed for early identification and referral to treatment. OBJECTIVE: This study aimed to determine if a panel of novel third-trimester plasma protein biomarkers in pregnant women can be used to identify those who have a high predisposed risk for perinatal mood and anxiety disorders within 3 months postpartum. STUDY DESIGN: We studied 52 women (n=34 with a risk for perinatal mood and anxiety disorders and n=18 controls) among whom mental health screening was conducted at 2 time points, namely in the third trimester and again at 3 months postdelivery. An elevated perinatal mood and anxiety disorder risk was identified by screening individuals with above-validated cutoffs for depression (Edinburgh Postnatal Depression Scale ≥12), anxiety (Overall Anxiety Severity and Impairment Scale ≥7), and/or posttraumatic stress disorder (Impact of Events Scale >26) at both time points. Plasma samples collected in the third trimester were screened using the aptamer-based SomaLogic SomaScan proteomic assay technology to evaluate perinatal mood and anxiety disorder-associated changes in the expression of 1305 protein analytes. Ingenuity Pathway Analysis was conducted to highlight pathophysiological relationships between perinatal mood and anxiety disorder-specific proteins found to be significantly up- or down-regulated in all subjects with perinatal mood and anxiety disorder and in those with perinatal mood and anxiety disorders and no preeclampsia. RESULTS: From a panel of 53 significant perinatal mood and anxiety disorder-associated proteins, a unique 20-protein signature differentiated perinatal mood and anxiety disorder cases from controls in a principal component analysis (P<.05). This protein signature included NCAM1, NRCAM, and NTRK3 that converge around neuronal signaling pathways regulating axonal guidance, astrocyte differentiation, and maintenance of GABAergic neurons. Interestingly, when we restricted the analysis to subjects without preeclampsia, a 30-protein signature differentiated perinatal mood and anxiety disorder cases from all controls without overlap on the principal component analysis (P<.001). In the nonpreeclamptic perinatal mood and anxiety disorder group, we observed increased expression of proteins, such as CXCL11, CXCL6, MIC-B, and B2MG, which regulate leucocyte migration, inflammation, and immune function. CONCLUSION: Participants with perinatal mood and anxiety disorders had a unique and distinct plasma protein signature that regulated a variety of neuronal signaling and proinflammatory pathways. Additional validation studies with larger sample sizes are needed to determine whether some of these molecules can be used in conjunction with traditional risk factors for the early detection of perinatal mood and anxiety disorders.