Clinical characteristics and changes in serum CXCL10 and CXCL16 levels in patients with severe mycoplasma pneumonia.

To explore the clinical characteristics and changes in serum CXCL10 and CXCL16 in patients with severe mycoplasma pneumonia, and to analyze the risk factors of severe mycoplasma pneumonia. About 258 children with acute mycoplasma pneumoniae pneumonia (MPP) admitted to the respiratory department of a certain hospital from January 2020 to December 2022 were selected as the study subjects. According to the severity of MPP, patients are divided into 2 groups, namely the mild illness group (Q group) and the severe illness group (Z group). The number of cases in these 2 groups of children is 167 and 91, respectively. The serum CXCL10, CXCL16, and other indicators of 2 groups are tested. Compared to group Q, patients in group Z have a higher proportion of extrapulmonary complications, longer cough time, longer shortness of breath, and longer wheezing time (P < .05). The serum CXCL16 is higher and the proportion of pleural effusion is higher (P < .01). There are more cases of fever, longer fever duration, longer hospital stay, higher serum CXCL10, and higher D-dimer levels (P < .001). The area under the curve of the probability curve for predicting severe mycoplasma pneumonia is 0.975 (P < .05). Children with severe mycoplasma pneumonia have significantly longer fever duration and hospital stay than those with mild symptoms. The serum levels of CXCL10 and CXCL16 are significantly elevated.

Evaluation of interleukins (IL-1α, IL-1Ra, IL-12, IL-17A, IL-31, and IL-33) and chemokines (CXCL10 and CXCL16) in the serum of male patients with ankylosing spondylitis.

BACKGROUND: A case-control study was performed to explore eight pro-inflammatory and anti-inflammatory cytokines, namely interleukin (IL)-1α, IL-1Ra (IL-1 receptor antagonist), IL-12, IL-17A, IL-31, IL-33, CXCL10 (C-X-C motif chemokine ligand 10), and CXCL16, with the aim to understand their role in ankylosing spondylitis (AS) pathogenesis and evaluate their utility as markers to differentiate between diseased and healthy individuals. Among these cytokines, IL-31 and CXCL16 have not been well studied in AS. PATIENTS AND METHODS: The study included 94 male patients with AS and 91 age-matched control males. Interleukin and chemokine levels were measured using ELISA kits. RESULTS: Serum levels of IL-17A, CXCL10, and CXCL16 were significantly elevated in patients compared to controls, while IL-31 levels were significantly decreased in patients. IL-17A, CXCL10, and CXCL16 were associated with an increased risk of AS, while IL-31 was associated with a decreased risk of disease (odds ratio = 1.22, 1.78, 1.14, and 0.89, respectively). As indicated by the area under the curve (AUC), IL-17A, IL-31, CXCL10, and CXCL16 were potential markers to differentiate between AS patients and controls (AUC = 0.877, 0.735, 0.8, and 0.7, respectively). IL-1α, IL-1Ra, IL-12, and IL-33 levels showed no significant variations between patients and controls. CONCLUSIONS: Among the eight cytokines examined, IL-17A, CXCL10, and CXCL16 were up-regulated in the serum of AS patients, while IL-31 was down-regulated. The levels of IL-1α, IL-1Ra, IL-12, and IL-33 showed no significant differences between patients and controls. Serum levels of all cytokines were not affected by disease duration, HLA-B27 positivity, or disease activity.

TRPM2-dependent autophagy inhibition exacerbates oxidative stress-induced CXCL16 secretion by keratinocytes in vitiligo.

Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte-derived chemokine C-X-C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2-mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12-Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank-binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2-restrained autophagy promotes CXCL16 secretion via the Atg5-TBK1-IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

Serum CXCL16: A new predictor of liver inflammation in patients with chronic hepatitis B.

The prompt initiation of antiviral therapy is essential in patients with chronic hepatitis B (CHB), especially when severe liver inflammation is detected. However, transcutaneous liver puncture, the gold standard for assessing liver inflammation, is invasive and its widespread application is limited. Therefore, there is an urgent need for more non-invasive markers to predict liver inflammation. In our retrospective cross-sectional study, which included 120 CHB patients and 31 healthy subjects, we observed a significant increase in serum chemokine C-X-C-motif ligand 16 (CXCL16) in CHB patients compared to healthy controls (p < .001). Notably, patients with severe inflammation (Scheuer's grade G ≥ 3, n = 26) exhibited a substantial increase in serum CXCL16 compared to those with non-severe inflammation (Scheuer's grade G < 3, n = 96) [(median, IQR), 0.42 (0.24-0.71) ng/mL vs. 1.01 (0.25-2.09) ng/mL, p < .001]. Furthermore, we developed a predictive model that combined CXCL16 with platelet count (PLT), alanine aminotransferase (ALT) and albumin (ALB) to accurately predict liver inflammation in CHB patients. This model was more effective than ALT alone in predicting liver inflammation (AUC, 0.92 vs. 0.81, p = .015). Additionally, using an HBV-transduced mouse model, we demonstrated that blocking CXCL16 led to a reduction in liver inflammation and impaired infiltration and function of natural killer T (NKT) and natural killer (NK) cells. These findings suggest that CXCL16 is a promising non-invasive biomarker of liver inflammation in CHB patients and may play a role in inducing liver inflammation via a NKT and NK cell pathway.

CXCL16 exacerbates Pseudomonas aeruginosa keratitis by promoting neutrophil activation.

Pseudomonas aeruginosa (PA) keratitis is a major cause of blindness characterized by corneal inflammation. In a murine model of PA keratitis, we assessed the detrimental effects of CXC chemokine ligand 16 (CXCL16). Quantitative PCR (qPCR), western blotting (WB) and immunofluorescence were used to measure the expression and localization of CXCL16 and its receptor, CXC chemokine receptor 6 (CXCR6). Clinical scores, plate counting, and hematoxylin-eosin staining were used to assess infection severity and its exacerbation by CXCL16. Immunofluorescence, myeloperoxidase assays, and flow cytometry were used to detect neutrophil activity and colocalization with CXCR6. WB and immunofluorescence were used to measure levels of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs). These methods also were used to measure the activation of downstream NF-κB signaling and its positive feedback on CXCL16 expression. ELISA, flow cytometry, and qPCR were used to measure the expression of CXCL2 and T helper 17 (Th17) cell-related genes. CXCL16 and CXCR6 expression was increased in infected corneas. Topical application of CXCL16 exacerbated keratitis by increasing corneal bacterial load and promoting neutrophil infiltration, whereas neutralizing antibody against CXCL16 had the opposite effect. CXCL16 also increased ROS and MMP levels. This neutrophil activation may be caused by its positive feedback with the NF-κB pathway and the upregulation of CXCL2 and Th17 cell related-genes. These data suggest that CXCL16 is an attractive therapeutic target for PA keratitis.

Identification of CXCL16 as a diagnostic biomarker for obesity and intervertebral disc degeneration based on machine learning.

Intervertebral disc degeneration (IDD) is the primary cause of neck and back pain. Obesity has been established as a significant risk factor for IDD. The objective of this study was to explore the molecular mechanisms affecting obesity and IDD by identifying the overlapping crosstalk genes associated with both conditions. The identification of specific diagnostic biomarkers for obesity and IDD would have crucial clinical implications. We obtained gene expression profiles of GSE70362 and GSE152991 from the Gene Expression Omnibus, followed by their analysis using two machine learning algorithms, least absolute shrinkage and selection operator and support vector machine-recursive feature elimination, which enabled the identification of C-X-C motif chemokine ligand 16 (CXCL16) as a shared diagnostic biomarker for obesity and IDD. Additionally, gene set variant analysis was used to explore the potential mechanism of CXCL16 in these diseases, and CXCL16 was found to affect IDD through its effect on fatty acid metabolism. Furthermore, correlation analysis between CXCL16 and immune cells demonstrated that CXCL16 negatively regulated T helper 17 cells to promote IDD. Finally, independent external datasets (GSE124272 and GSE59034) were used to verify the diagnostic efficacy of CXCL16. In conclusion, a common diagnostic biomarker for obesity and IDD, CXCL16, was identified using a machine learning algorithm. This study provides a new perspective for exploring the possible mechanisms by which obesity impacts the development of IDD.

CXCL5 and CXCL14, but not CXCL16 as potential biomarkers of colorectal cancer.

Experts emphasize that colorectal cancer (CRC) incidence and mortality are increasing. That is why its early detection is of the utmost importance. Patients with cancer diagnosed in earlier stages have a better prognosis and a chance for faster implementation of treatment. Consequently, it is vital to search for new parameters that could be useful in its diagnosis. Therefore, we evaluated the usefulness of CXCL5, CXCL14 and CXCL16 in serum of 115 participants (75 CRC patients and 40 healthy volunteers). Concentrations of all parameters were measured using Luminex. CRP (C-reactive protein) levels were determined by immunoturbidimetry, while levels of classical tumor markers were measured using CMIA (Chemiluminescence Microparticle Immunoassay). Concentrations of CXCL5 were statistically higher in the CRC group when compared to healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and area under the ROC curve (AUC) of CXCL5 and CXCL14 were higher than those of CA 19-9. Obtained results suggest the usefulness of CXCL5 and CXCL16 in the determination of distant metastases and differentiation between TNM (Tumor-Node-Metastasis) stages, as well as the usefulness of CXCL14 and CRP combination in CRC detection (primary or recurrence). However, further studies concerning their role in CRC progression are crucial to confirm and explain their diagnostic utility and clinical application as biomarkers.

Systemic virus infection results in CD8 T cell recruitment to the retina in the absence of local virus infection.

During recent years, evidence has emerged that immune privileged sites such as the CNS and the retina may be more integrated in the systemic response to infection than was previously believed. In line with this, it was recently shown that a systemic acute virus infection leads to infiltration of CD8 T cells in the brains of immunocompetent mice. In this study, we extend these findings to the neurological tissue of the eye, namely the retina. We show that an acute systemic virus infection in mice leads to a transient CD8 T cell infiltration in the retina that is not directed by virus infection inside the retina. CD8 T cells were found throughout the retinal tissue, and had a high expression of CXCR6 and CXCR3, as also reported for tissue residing CD8 T cells in the lung and liver. We also show that the pigment epithelium lining the retina expresses CXCL16 (the ligand for CXCR6) similar to epithelial cells of the lung. Thus, our results suggest that the retina undergoes immune surveillance during a systemic infection, and that this surveillance appears to be directed by mechanisms similar to those described for non-privileged tissues.

Role of the CXCR6/CXCL16 axis in autoimmune diseases.

The C-X-C motif ligand 16, or CXCL16, is a chemokine that belongs to the ELR - CXC subfamily. Its function is to bind to the chemokine receptor CXCR6, which is a G protein-coupled receptor with 7 transmembrane domains. The CXCR6/CXCL16 axis has been linked to the development of numerous autoimmune diseases and is connected to clinical parameters that reflect disease severity, activity, and prognosis in conditions such as multiple sclerosis, autoimmune hepatitis, rheumatoid arthritis, Crohn's disease, and psoriasis. CXCL16 is expressed in various immune cells, such as dendritic cells, monocytes, macrophages, and B cells. During autoimmune diseases, CXCL16 can facilitate the adhesion of immune cells like monocytes, T cells, NKT cells, and others to endothelial cells and dendritic cells. Additionally, sCXCL16 can regulate the migration of CXCR6-expressing leukocytes, which includes CD8+ T cells, CD4+ T cells, NK cells, constant natural killer T cells, plasma cells, and monocytes. Further investigation is required to comprehend the intricate interactions between chemokines and the pathogenesis of autoimmune diseases. It remains to be seen whether the CXCR6/CXCL16 axis represents a new target for the treatment of these conditions.

TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis.

Pustular psoriasis (PP) is a chronic inflammatory disease associated with multiple complications, often with hyperthermia and hypoproteinemia, and its continued progression can be life-threatening. Toll-like receptor 7 (TLR7) induces dendritic cell (DC) production of inflammatory factors that exacerbate the inflammatory response in PP. A membrane-bound chemokine expressed on DCs, CXC motif chemokine ligand 16 (CXCL16) is overexpressed in PP lesions, and neutrophils express its receptor CXC chemokine receptor 6 (CXCR6). There are few studies on the PP immune microenvironment and it is unclear whether TLR7 and CXCL16 can be used as targets in PP therapy. Skin tissue (n = 5) and blood (n = 20) samples were collected from PP and healthy normal controls. The skin tissue transcriptome was analyzed to obtain the differentially expressed genes, and the immune microenvironment was deciphered using pathway enrichment. Tissue sequencing analysis indicated that TLR7, CXCL16, DCs, and neutrophils were involved in the PP process. The enzyme-linked immunosorbent assay, reverse transcription-PCR, and scoring table results demonstrated that TLR7 induced DC secretion of CXCL16, which enabled neutrophil activation of the secretion of the inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α). The co-culture of neutrophils with DCs treated with TLR7 inhibitor or TLR7 agonist demonstrated that TLR7 regulated neutrophil activation, migration, and apoptosis. We constructed imiquimod-induced psoriasis-like skin lesions in wild-type, Cd11c-Cre Myd88f/f, and Mrp8-Cre Cxcr6f/f mice. The mouse models suggested that TLR7 might influence DC release of CXCL16 and neutrophil proinflammatory effects by interfering with the myeloid differentiation primary response gene 88 (MyD88) signaling pathway. In conclusion, the TLR7-MyD88-DC-CXCL16 axis is an important mechanism that promotes neutrophil migration to PP skin lesions and stimulates the inflammatory response.

sCXCL16 as a prognostic biomarker for COVID-19 outcome.

As elevated levels of the soluble CXCL16 (sCXCL16) chemokine have been reported in severe coronavirus disease 2019 (COVID-19) patients, this study examined whether sCXCL16 concentration on the first day of hospitalization predicted death in COVID-19 patients. A total of 76 patients with COVID-19 were admitted to the Military Hospital of Tunis, Tunisia, between October 2020 and April 2021, and later classified as survivors or nonsurvivors based on their outcomes. At admission, the groups were matched by age, gender, comorbidities, and the percentage of patients with moderate conditions. On the first day of admission, serum's sCXCL16 concentrations were measured using a magnetic-bead assay. There was an eightfold increase in serum sCXCL16 levels in the nonsurvivors' group (3661.51 ± 2464.87 pg/mL vs. 454.3 ± 338.07 pg/mL, p < 0.0001). For the optimal cutoff value of sCXCL16 at 2095 pg/mL, we found a 94.6% sensitivity and a 97.4% specificity, with an area under curve of 0.981 (p = 5.03E-08; 95% confidence interval [95% CI]: 0.951-1.0114). Considering the risk of death at a concentration above the threshold, the unadjusted odds ratio was 36 (p < 0.0001). The adjusted odd ratio was estimated at 1.003 (p < 0.0001; 95% CI: 1.002-1.004). Finally, there was a significant difference between survival and nonsurvival groups in leukocyte numbers (p = 0.006), lymphocytes (p = 0.001), polymorphonuclear neutrophils (p = 0.001), and C-reactive protein levels (p = 0.007), except for monocytes (p = 0.881). Based on these results, sCXCL16 level could be used for detecting nonsurvival COVID-19 patients. Therefore, we recommend assessing this marker in hospitalized COVID-19 patients.

Upregulation of IL-33, CCL2, and CXCL16 levels in Brazilian pregnant women infected by Toxoplasma gondii.

Congenital toxoplasmosis can cause neurological and eye damage, behavioral alterations, or death in fetuses or babies born to Toxoplasma gondii-infected women. Several pieces of evidence suggest that socioeconomic, environmental, and inflammatory patterns linked to the maternal immune response partly drive the pathogenesis of this disease. However, immunoregulation induced by T. gondii infection during gestation is not completely understood. The aim of this study was to assess the association between T. gondii seropositivity and concentrations of plasma markers (CCL2, CXCL16, IL-17, and IL-33) in Brazilian pregnant women. Inflammatory markers were measured by immunoassays in the plasma of 131 pregnant women (13 to 46 years old). The prevalence of T. gondii infections was 45.8% (n = 60) in this population. The concentrations of CCL2, CXCL16, and IL-33 were higher in T. gondii-seropositive than in seronegative pregnant women, while the opposite was observed for IL-17 levels. In IgG+ women, a strong correlation between IL-17 and IL-33 (r = 0.7508, p = 0.0001) and a moderate correlation between CXCL16/IL-17 (r = 0.7319, p = 0.0001) and CXCL16/CCL2 (r = 0.3519, p = 0.0098) was observed. In uninfected women, a strong correlation was found between IL-17 and CXCL16 (r = 0.6779, p = 0.0001) but moderate between IL-17 and IL-33 (r = 0.4820, p = 0.0001). In summary, our data suggest that plasma upregulation of CCL2, CXCL16, and IL-33 might exert a potential protective role in the mother/fetus/parasite axis and, in addition, multiparous women are more likely to be infected with T. gondii than primiparous women.

Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer.

Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1's role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.

ELK3-CXCL16 axis determines natural killer cell cytotoxicity via the chemotactic activity of CXCL16 in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Here, we show that targeting an ETS transcription factor ELK3 (ELK3) recruits immune cells including natural killer (NK) cells into tumors via the chemotactic activity of chemokine. ELK3 depletion increases CXCL16 expression level and promotes NK cell cytotoxicity through CXCL16-mediated NK cell recruitment in TNBC. In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Our findings demonstrate that the ELK3-CXCL16 axis modulates NK cell recruitment to increase NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID.

BACKGROUND: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). METHODS: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. RESULTS: Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. CONCLUSIONS: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

CXCL16 Promotes Ly6Chigh Monocyte Infiltration and Impairs Heart Function after Acute Myocardial Infarction.

High CXCL16 levels during acute cardiovascular events increase long-term mortality. However, the mechanistic role of CXCL16 in myocardial infarction (MI) is unknown. Here we investigated the role of CXCL16 in mice with MI injury. CXCL16 deficiency increased the survival of mice after MI injury, and inactivation of CXCL16 resulted in improved cardiac function and decreased infarct size. Hearts from CXCL16 inactive mice exhibited decreased infiltration of Ly6Chigh monocytes. In addition, CXCL16 promoted the macrophage expression of CCL4 and CCL5. Both CCL4 and CCL5 stimulated Ly6Chigh monocyte migration, and CXCL16 inactive mice had a reduced expression of CCL4 and CCL5 in the heart after MI. Mechanistically, CXCL16 promoted CCL4 and CCL5 expression by activating the NF-κB and p38 MAPK signaling pathways. Anti-CXCL16 neutralizing Ab administration inhibited Ly6Chigh monocyte infiltration and improved cardiac function after MI. Additionally, anti-CCL4 and anti-CCL5 neutralizing Ab administration inhibited Ly6Chigh monocyte infiltration and improved cardiac function after MI. Thus, CXCL16 aggravated cardiac injury in MI mice by facilitating Ly6Chigh monocyte infiltration.

Metformin attenuates symptoms of osteoarthritis: role of genetic diversity of Bcl2 and CXCL16 in OA.

OBJECTIVE: This study aimed to evaluate the effectiveness of metformin versus placebo in overweight patients with knee osteoarthritis (OA). In addition, to assess the effects of inflammatory mediators and apoptotic proteins in the pathogenesis of OA, the genetic polymorphisms of two genes, one related to apoptosis (rs2279115 of Bcl-2) and the other related to inflammation (rs2277680 of CXCL-16), were investigated. METHODS: In this double-blind placebo-controlled clinical trial, patients were randomly divided to two groups, one group receiving metformin (n = 44) and the other one receiving an identical inert placebo (n = 44) for 4 consecutive months (starting dose 0.5 g/day for the first week, increase to 1 g/day for the second week, and further increase to 1.5 g/day for the remaining period). Another group of healthy individuals (n = 92) with no history and diagnosis of OA were included in this study in order to evaluate the role of genetics in OA. The outcome of treatment regimen was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The frequency of variants of rs2277680 (A181V) and rs2279115 (938C>A) were determined in extracted DNAs using PCR-RFLP method. RESULTS: Our results indicated an increase in scores of pain (P ≤ 0.0001), activity of daily living (ADL) (P ≤ 0.0001), sport and recreation (Sport/Rec) (P ≤ 0.0001), and quality of life (QOL) (P = 0.003) and total scores of the KOOS questionnaire in the metformin group compared to the placebo group. Susceptibility to OA was associated with age, gender, family history, CC genotype of 938C>A (Pa = 0.001; OR = 5.2; 95% CI = 2.0-13.7), and GG+GA genotypes of A181V (Pa = 0.04; OR = 2.1; 95% CI = 1.1-10.5). The C allele of 938C>A (Pa = 0.04; OR = 2.2; 95% CI = 1.1-9.8) and G allele of A181V (Pa = 0.02; OR = 2.2; 95% CI = 1.1-4.8) were also associated with OA. CONCLUSION: Our findings support the possible beneficial effects of metformin on improving pain, ADL, Sport/Rec, and QOL in OA patients. Our findings support the association between the CC genotype of Bcl-2 and GG+GA genotypes of CXCL-16 and OA.

Convergent transcriptomic and genomic evidence supporting a dysregulation of CXCL16 and CCL5 in Alzheimer's disease.

BACKGROUND: Neuroinflammatory factors, especially chemokines, have been widely reported to be involved in the pathogenesis of Alzheimer's disease (AD). It is unclear how chemokines are altered in AD, and whether dysregulation of chemokines is the cause, or the consequence, of the disease. METHODS: We initially screened the transcriptomic profiles of chemokines from publicly available datasets of brain tissues of AD patients and mouse models. Expression alteration of chemokines in the blood from AD patients was also measured to explore whether any chemokine might be used as a potential biomarker for AD. We further analyzed the association between the coding variants of chemokine genes and genetic susceptibility of AD by targeted sequencing of a Han Chinese case-control cohort. Mendelian randomization (MR) was performed to infer the causal association of chemokine dysregulation with AD development. RESULTS: Three chemokine genes (CCL5, CXCL1, and CXCL16) were consistently upregulated in brain tissues from AD patients and the mouse models and were positively correlated with Aß and tau pathology in AD mice. Peripheral blood mRNA expression of CXCL16 was upregulated in mild cognitive impairment (MCI) and AD patients, indicating the potential of CXCL16 as a biomarker for AD development. None of the coding variants within any chemokine gene conferred a genetic risk to AD. MR analysis confirmed a causal role of CCL5 dysregulation in AD mediated by trans-regulatory variants. CONCLUSIONS: In summary, we have provided transcriptomic and genomic evidence supporting an active role of dysregulated CXCL16 and CCL5 during AD development.

CXCR6 Mediates Pressure Overload-Induced Aortic Stiffness by Increasing Macrophage Recruitment and Reducing Exosome-miRNA29b.

Aortic stiffness is an independent risk factor for aortic diseases such as aortic dissection which commonly occurred with aging and hypertension. Chemokine receptor CXCR6 is critically involved in vascular inflammation and remodeling. Here, we investigated whether and how CXCR6 plays a role in aortic stiffness caused by pressure overload. CXCR6-/- and WT mice underwent transverse aortic constriction (TAC) surgery for 8 weeks. CXCR6 deficiency significantly improved TAC-induced aortic remodeling and endothelial dysfunction by decreasing CD11c+ macrophage infiltration, suppressing VCAM-1 and ICAM-1, reducing collagen deposition, and downregulating MMP12 and osteopontin in the aorta. Consistently, blocking the CXCL16/CXCR6 axis also reduced aortic accumulation of CD11c+ macrophages and vascular stiffness but without affecting the release of TNF-α and IL-6 from the aorta. Furthermore, pressure overload inhibited aortic release of exosomes, which could be reversed by suppressing CXCR6 or CXCL16. Inhibition of exosome release by GW4869 significantly aggravated TAC-induced aortic calcification and stiffness. By exosomal microRNA microarray analysis, we found that microRNA-29b was significantly reduced in aortic endothelial cells (AECs) receiving TAC. Intriguingly, blocking the CXCL16/CXCR6 axis restored the expression of miR-29b in AECs. Finally, overexpression of miR-29b significantly increased eNOS and reduced MMPs and collagen in AECs. By contrast, antagonizing miR-29b in vivo further enhanced TAC-induced expressions of MMP12 and osteopontin, aggravated aortic fibrosis, calcification, and stiffness. Our study demonstrated a key role of the CXCL16/CXCR6 axis in macrophage recruitment and macrophage-mediated aortic stiffness under pressure overload through an exosome-miRNAs-dependent manner.

Reduced expression of CXCL16/CXCR6 is involved in the pathogenesis of hidradenitis suppurativa.

Mutations in the γ-secretase complex have been well-described in familial hidradenitis suppurativa (HS). No gene mutations have been identified in sporadic HS, which comprises 60%-70% of all HS cases. Obesity and smoking are risk factors for HS and are closely related to DNA methylation, an essential epigenetic phenomenon. Hence, we hypothesized that epigenetic modifications might be involved in sporadic HS. To investigate genes with aberrant methylation in sporadic HS cases and assess their expression in skin lesions and blood from patients with HS. Skin lesion samples and corresponding normal skin were obtained from three patients with HS and subjected to whole-genome DNA methylation sequencing. Blood samples were collected from 20 patients with HS and 20 healthy controls (HCs). The HS mouse model was established by applying tamoxifen to NcstnΔKC mice. Target gene expression was analysed by immunohistochemistry, immunofluorescence, western blotting, enzyme-linked immunosorbent assay (ELISA) and semiquantitative real-time polymerase chain reaction (RT-qPCR). Among 10 807 differentially methylated genes, we filtered 2101 genes with hypermethylated promoter regions, and following bioinformatics analyses, we focused on CXC chemokine ligand 16 (CXCL16). Subsequent functional experiments confirmed the downregulation of CXCL16 and its receptor, CXC chemokine receptor (CXCR) 6, in skin tissue from HS patients and NcstnΔKC mice. Serum CXCL16 concentrations were also significantly decreased in patients with HS. Our data revealed the downregulation of CXCL16 and CXCR6 in HS.