Involvement of CXCL10 rs4256246, CXCR4 rs2228014, CCR2 rs1799864 and CXCL16 rs2277680 in the Predisposition to Schizophrenia.

Chemokine ligands and their receptors have acquired less attention than pro- and anti-inflammatory cytokines in schizophrenia (SCZ). Thus, we aimed to examine the impact of functional polymorphisms of the chemokine genes CXCL10, CXCL16, CXCR4, and CCR2 in the development of SCZ. Using PCR-RFLP, we analyzed the selected polymorphisms in a Tunisian cohort composed of 200 patients with SCZ and 200 healthy controls. Our preliminary data suggest that the minor allele A of CXCL10 rs4256246 is significantly associated with likelihood of SCZ (PAdjusted = 0.00002) and more precisely to paranoid patients with late-onset SCZ (PAdjusted = 0.0007). However, the mutated allele T of CXCR4 rs2228014 showed a significant protective impact against SCZ (PAdjusted = 0.000007) and especially to male sex (PAdjusted = 0.000003). This effect persists among the undifferentiated patients with early-onset SCZ (PAdjusted = 0.002). Following the stratified analyses, CCR2 rs1799864 and CXCL16 rs2277680 were significantly correlated with the clinical symptoms among disorganized patients. As regards haplotype analysis, we noted that GATG haplotype was associated with protection against SCZ (PAdjusted = 0.0087) but the AGCG haplotype was correlated with susceptibility to this disease (PAdjusted = 0.014). Our preliminary results suggested that CXCL10 rs4256246 enhanced susceptibility to SCZ, while CXCR4 rs2228014 seemed to be protective factor. Furthermore, we identified a substantial correlation between CCR2 rs1799864 and CXCL16 rs2277680 with the clinical signs of the disorder. To validate these results and clarify the functional significance of the targeted polymorphisms in SCZ, more independent research is needed.

Silencing CXCL16 alleviate neuroinflammation and M1 microglial polarization in mouse brain hemorrhage model and BV2 cell model through PI3K/AKT pathway.

Neuroinflammation and microglia polarization play pivotal roles in brain injury induced by intracerebral hemorrhage (ICH). Despite the well-established involvement of CXC motif chemokine ligand 16 (CXCL16) in regulating inflammatory responses across various diseases, its specific functions in the context of neuroinflammation and microglial polarization following ICH remain elusive. In this study, we investigated the impact of CXCL16 on neuroinflammation and microglia polarization using both mouse and cell models. Our findings revealed elevated CXCL16 expression in mice following ICH and in BV2 cells after lipopolysaccharide (LPS) stimulation. Specific silencing of CXCL16 using siRNA led to a reduction in the expression of neuroinflammatory factors, including IL-1ß and IL-6, as well as decreased expression of the M1 microglia marker iNOS. Simultaneously, it enhanced the expression of anti-inflammatory factors such as IL-10 and the M2 microglia marker Arg-1. These results were consistent across both mouse and cell models. Intriguingly, co-administration of the PI3K-specific agonist 740 Y-P with siRNA in LPS-stimulated cells reversed the effects of siRNA. In conclusion, silencing CXCL16 can positively alleviate neuroinflammation and M1 microglial polarization in BV2 inflammation models and ICH mice. Furthermore, in BV2 cells, this beneficial effect is mediated through the PI3K/Akt pathway. Inhibition of CXCL16 could be a novel approach for treating and diagnosing cerebral hemorrhage.

MiR-625-5p is a potential therapeutic target in sepsis by regulating CXCL16/CXCR6 axis and endothelial barrier.

BACKGROUND: MicroRNA plays an important role in the progression of sepsis. We found a significant increase of in miR-625-5p expression in the blood of patients with sepsis, and lipopolysaccharide (LPS)-stimulated EA.hy926 cells. To date, little is known about the specific biological function of miR-625-5p in sepsis. METHODS: Changes in miR-625-5p expression were verified through quantitative real-time polymerase chain reaction in 45 patients with sepsis or septic shock and 30 healthy subjects. In vitro, EA.hy926 cells were treated with LPS. Transendothelial electrical resistance assay and FITC-dextran were used in evaluating endothelial barrier function. RESULTS: Herein, patients with sepsis or septic shock had significantly higher miR-625-5p expression levels, chemokine (C-X-C motif) ligand 16 (CXCL16) levels, and glycocalyx components than the healthy controls, and miR-625-5p level was positively correlated with disease. Kaplan-Meier analysis demonstrated a strong association between miR-625-5p level and 28-day mortality. Furthermore, the miR-625-5p inhibitor significantly alleviated LPS-induced endothelial barrier injury in vitro. Then, miR-625-5p positively regulated CXCL16 and down-regulated miR-625-5p attenuated CXCL16 transcription and expression in EA.hy926 cells. CXCL16 knockout significantly alleviated vascular barrier dysfunction in the LPS-induced EA.hy926 cells. sCXCL16 treatment in EA.hy926 cells significantly increased endothelial hyperpermeability by disrupting endothelial glycocalyx, tight junction proteins, and adherens junction proteins through the modulation of C-X-C chemokine receptor type 6 (CXCR6). CONCLUSIONS: Increase in miR-625-5p level may be an effective biomarker for predicting 28-day mortality in patients with sepsis/septic shock. miR-625-5p is a critical pathogenic factor for endothelial barrier dysfunction in LPS-induced EA.hy926 cells because it activates the CXCL16/CXCR6 axis.

Washed microbiota transplantation promotes homing of group 3 innate lymphoid cells to the liver via the CXCL16/CXCR6 axis: a potential treatment for metabolic-associated fatty liver disease.

Despite the observed decrease in liver fat associated with metabolic-associated fatty liver disease (MAFLD) in mice following fecal microbiota transplantation, the clinical effects and underlying mechanisms of washed microbiota transplantation (WMT), a refined method of fecal microbiota transplantation, for the treatment of MAFLD remain unclear. In this study, both patients and mice with MAFLD exhibit an altered gut microbiota composition. WMT increases the levels of beneficial bacteria, decreases the abundance of pathogenic bacteria, and reduces hepatic steatosis in MAFLD-affected patients and mice. Downregulation of the liver-homing chemokine receptor CXCR6 on ILC3s results in an atypical distribution of ILC3s in patients and mice with MAFLD, characterized by a significant reduction in ILC3s in the liver and an increase in ILC3s outside the liver. Moreover, disease severity is negatively correlated with the proportion of hepatic ILC3s. These hepatic ILC3s demonstrate a mitigating effect on hepatic steatosis through the release of IL-22. Mechanistically, WMT upregulates CXCR6 expression on ILC3s, thereby facilitating their migration to the liver of MAFLD mice via the CXCL16/CXCR6 axis, ultimately contributing to the amelioration of MAFLD. Overall, these findings highlight that WMT and targeting of liver-homing ILC3s could be promising strategies for the treatment of MAFLD.

CD8 T cells induce the peritubular capillary rarefaction during AKI to CKD transition.

Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.

Soluble CXCL16 is a prognostic biomarker associated with rapidly progressive interstitial lung disease complicated with dermatomyositis.

OBJECTIVES: Rapidly progressive interstitial lung disease (RPILD) in patients with dermatomyositis (DM) significantly impacts prognosis, leading to high mortality rates. Although several indicators have been demonstrated to strongly correlate with the risk of developing RPILD, their clinical utility still needs to be investigated. The objective of this study was to investigate the clinical significance of soluble CXCL16 (sCXCL16) in DM patients complicated with RPILD. METHODS: Serum sCXCL16 was measured by enzyme-linked immunosorbent assay in 96 patients with DM and 55 matching healthy donors. Correlations between sCXCL16 levels and clinical features, laboratory examinations and the predictive value of baseline sCXCL16 level for RPILD were analysed. RESULTS: The serum sCXCL16 levels were significantly higher in patients with DM (n = 96, 3.264 ± 1.516 ng/mL) compared with healthy donors (n = 55, 1.781 ± 0.318 ng/mL), especially in DM complicated with RPILD (n = 31, 4.441 ± 1.706 ng/mL). The sCXCL16 levels were positively correlated with levels of serum ferritin, C reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, hydroxybutyrate dehydrogenase, and negatively correlated with peripheral lymphocytes percentage, but showed no correlation with levels of anti-melanoma differentiation-associated gene 5 antibody, Krebs von den Lungen-6 or creatine kinase. Multivariable analysis showed that elevated sCXCL16 was an independent prognostic factor for poor prognosis of RPILD in patients with DM. The 2-year survival rate was significantly lower in patients with high sCXCL16 level than in those with low sCXCL16 level. CONCLUSION: A higher serum sCXCL16 level was identified as a predictive biomarker of RPILD in patients with DM, and closely associated with poor prognosis.

CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity.

The pancreatic islet microenvironment is highly oxidative, rendering ß cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.

Bortezomib restrains M2 polarization and reduces CXCL16-associated CXCR6+CD4 T cell chemotaxis in bleomycin-induced pulmonary fibrosis.

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.

The role of the CXCR6/CXCL16 axis in the pathogenesis of fibrotic disease.

CXC chemokine receptor 6 (CXCR6), a seven-transmembrane domain G-protein-coupled receptor, plays a pivotal regulatory role in inflammation and tissue damage through its interaction with CXC chemokine ligand 16 (CXCL16). This axis is implicated in the pathogenesis of various fibrotic diseases and correlates with clinical parameters that indicate disease severity, activity, and prognosis in organ fibrosis, including afflictions of the liver, kidney, lung, cardiovascular system, skin, and intestines. Soluble CXCL16 (sCXCL16) serves as a chemokine, facilitating the migration and recruitment of CXCR6-expressing cells, while membrane-bound CXCL16 (mCXCL16) functions as a transmembrane protein with adhesion properties, facilitating intercellular interactions by binding to CXCR6. The CXCR6/CXCL16 axis is established to regulate the cycle of damage and repair during chronic inflammation, either through modulating immune cell-mediated intercellular communication or by independently influencing fibroblast homing, proliferation, and activation, with each pathway potentially culminating in the onset and progression of fibrotic diseases. However, clinically exploiting the targeting of the CXCR6/CXCL16 axis requires further elucidation of the intricate chemokine interactions within fibrosis pathogenesis. This review explores the biology of CXCR6/CXCL16, its multifaceted effects contributing to fibrosis in various organs, and the prospective clinical implications of these insights.

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.