Elevated cerebrospinal fluid Galectin-9 is associated with central nervous system immune activation and poor cognitive performance in older HIV-infected individuals.

We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (ß = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.

Elevated cerebrospinal fluid galectin-3 and associated cytokines after severe traumatic brain injury in patients.

This study aimed to investigate the galectin-3 and associated cytokines levels in the cerebrospinal fluid (CSF) of severe traumatic brain injury (sTBI) patients. Temporal CSF expression of galectin-3 and associated cytokines levels in sTBI patients within 1-week post-injury were studied using the multiplex bead array. STBI patient group was stratified using the Modified Rankin Score (mRS) into 3 groups: mRS 6 (died), mRS 5 (severely disabled) and mRS 1-4 (mild-to-moderately disabled) group. Analysis for bead array data using Kruskal-Wallis test with post hoc Dunn's multiple comparisons test, and temporal changes and correlation analysis using Spearman's correlation were carried out. At day 1 post-injury, CSF galectin-3 and interleukin-6 (IL-6), interleukin-10 (IL-10), cysteine-cysteine motif chemokine ligand-2 (CCL-2), and cysteine-cysteine motif chemokine ligand-20 (CCL-20), but not interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) levels were significantly elevated in mRS 5 group compared to non-TBI controls. Temporal correlation analysis at 1-7 days showed decreased IL-10 level in the mRS 6 group, decreased IL-10 and CCL-2 levels in mRS 5 group, and decreased IL-6, CCL-2, and CCL-20 levels in the mRS 1-4 group. Receiver operating characteristic curve analyses revealed a significant area under the curve for comparison between mRS 6 and mRS 5 groups for galectin-3 and IL-6. No significant differences in sex, age, Glasgow Coma Scale score, C-reactive protein levels and types of TBI-induced hemorrhages were observed between the groups. CSF galectin-3 and associated cytokines, especially IL-6, CCL-2 and CCL-20 levels were different within sub-groups of sTBI patients, suggesting their potential use in sTBI prognostics.

Galectin-9-like from Angiostrongylus cantonensis young adult worms modulates eosinophil chemotaxis in vitro.

BACKGROUND/PURPOSE: Eosinophils are recruited to the brain of mice after infection with Angiostrongylus canonensis. Several factors produced by infected mice are well known playing the role to chemoattract eosinophils from the blood into the brain. The purpose of this study is to investigate whether Angiostronylus cantonensis young-adult worms (AcYA) have components which have eosinophilic chemotactic activity. METHODS: Eosinophil chemotactic activity of AcYA was tested by Boyden blind-well chamber technique. The components of AcYA were analysed by SDS-PAGE and Mass spectrometry. Furthermore, galectin-9 in the cerebrospinal fluid (CSF) of infected mice and galectin-9-like in AcYA were measured by ELISA technic and also were recognized by western blot analysis respectively. RESULTS: Excretory-secretory products of AcYA did not show eosinophil chemotactic activity. However, the extracts of AcYA showed protein concentration-dependent eosinophil chemotactic activity and reached the peak at the 24 µg/ml. The eosinophil chemotactic activity was significantly reduced by lactose. The components of AcYA at molecular weights of approximatively 15 kDa and 35 kDa showed several galectins component in Mass spectrometric analysis. Furthermore, galectin-9-like in AcYA was recognized by ELISA and western blot analysis. In parallel with increase of galectin-9 in the CSF, eosinophils were also significantly increased in mouse after infected with A. cantonensis. CONCLUSION: Galectin-9-like in AcYA and galectin-9 in mouse CSF were confirmed demonstrating eosinophil chemotactic activity both in vitro study and in the infection of mouse in this study.

Galectin-9 as a biomarker for disease activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by elevated interferon (IFN) signature genes. Galectin-9 (Gal-9) is a ß-galactoside-binding lectin that is reportedly useful as a biomarker for IFN gene signatures. In a cross-sectional study of Japanese patients with recent-onset SLE, we aimed to determine whether raised serum Gal-9 levels were associated with the disease activity or organ damage seen in SLE patients. METHODS: The current study included 58 Japanese patients with SLE and 31 age-matched healthy individuals. Disease activity and organ damage were assessed using SLE Disease Activity 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) damage index. Serum and cerebrospinal fluid (CSF) Gal-9 concentrations were quantified using ELISA. Correlation analyses between Gal-9 and clinical parameters including disease activity were performed. RESULTS: Serum levels of Gal-9 were significantly increased in patients with SLE compared with the control group (16.6 ng/ml, [interquartile range (IQR); 3.6-59.7] versus 4.74 ng/ml, [IQR; 3.0-9.5], p<0.0001). Gal-9 was significantly correlated with disease activity measures in the SLEDAI-2K. Serum Gal-9 levels were significantly greater in patients with SLE-related organ involvement (23.1 ng/ml, [IQR; 5.1-59.7] versus 12.5ng/ml, [IQR; 3.6-39.0], p = 0.013). Whereas there was no difference in serum levels of CXCL10 or M2BPGi between patients with and without SLE-related organ involvement. Serum levels of Gal-9 were significantly higher in SLE patients with active renal involvement determined by BILAG renal score (A-B) compared to those without active renal involvement (C-E). Whereas there was no significant difference in serum levels of Gal-9 between SLE patients with or without active other organ involvements (neurological or hematological) determined by BILAG score. SLE patients with detectable circulating IFN-α had raised serum Gal-9 levels. Levels of Gal-9 were significantly higher in the CSF from patients with recent-onset neuropsychiatric SLE (NPSLE) than in those from non-SLE controls (3.5 ng/ml, [IQR; 1.0-27.2] versus 1.2 ng/ml, [IQR; 0.9-2.1], p = 0.009). CONCLUSIONS: Gal-9 could be a serologic marker of disease activity and organ involvement in SLE patients. Future studies evaluating the role of Gal-9 in the SLE phenotype may provide insights into SLE pathogenesis.

Exosomal LGALS9 in the cerebrospinal fluid of glioblastoma patients suppressed dendritic cell antigen presentation and cytotoxic T-cell immunity.

Glioblastoma multiforme (GBM) is highly invasive, with a high recurrence rate and limited treatment options, and is the deadliest glioma. Exosomes (Exos) have attracted much attention in the diagnosis and treatment of GBM and are expected to address the severe limitations of biopsy conditions. Exos in the cerebrospinal fluid (CSF) have great potential in GBM dynamic monitoring and intervention strategies. Here, we evaluated the difference in the proteome information of Exos from the CSF (CSF-Exos) between GBM patients and low-grade glioma patients, and the correlations between GBM-CSF-Exos and immunosuppressive properties. Our results indicates that GBM-CSF-Exos contained a unique protein, LGALS9 ligand, which bound to the TIM3 receptor of dendritic cells (DCs) in the CSF to inhibit antigen recognition, processing and presentation by DCs, leading to failure of the cytotoxic T-cell-mediated antitumor immune response. Blocking the secretion of exosomal LGALS9 from GBM tumors could cause mice to exhibit sustained DC tumor antigen-presenting activity and long-lasting antitumor immunity. We concluded that GBM cell-derived exosomal LGALS9 acts as a major regulator of tumor progression by inhibiting DC antigen presentation and cytotoxic T-cell activation in the CSF and that loss of this inhibitory effect can lead to durable systemic antitumor immunity.

Cerebrospinal fluid concentration of Galectin-9 is increased in secondary progressive multiple sclerosis.

Galectin-9 is produced by activated astrocytes, induces a pro-inflammatory response in microglia and may be important to the pathogenesis of secondary progressive MS. In this study, Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on T1-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count.