Plasma CCL2 Research Articles

Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages

ObjectiveWe assessed the role of a systemic lupus erythematosus causal hypofunctional variant, neutrophil cytosolic factor 1 (NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc).MethodsAssociation of NCF1-H90 with SSc was performed in...

Neuroserpin, IL-33 and IL-17A as potential markers of mild symptoms of depressive syndrome in Toxoplasma gondii-infected pregnant women.

Depressive syndrome (DS) is a common complication during pregnancy and the postpartum period, and is triggered by multiple organic/genetic and environmental factors. Clinical and biochemical follow-up is essential for the early diagnosis and prognosis of DS. The protozoan Toxoplasma gondii causes infectious damage to the fetus during parasite primary-infection. However, in long-term infections, pregnant women develop immune protection to protect the fetus, although they remain susceptible to pathological or inflammatory effects induced by T. gondii. This study aimed to investigate plasma inflammatory biomarkers in pregnant women seropositive and seronegative for T. gondii, with diagnoses of minor and moderate/severe DS. Pregnant women (n=45; age=18-39 years) were recruited during prenatal care at health centers in Ouro Preto, Minas Gerais, Brazil. Participants were asked to complete a socio-demographic questionnaire to be submitted to well-standardized DS scale calculators (Beck Depression Inventory Questionnaire, Edinburgh Postnatal Depression Scale, and Major Depressive Episode Module). Additionally, 4 mL of blood was collected for plasma neuroserpin, CCL2, IL-17A, and IL-33 analysis. Pregnant volunteers with chronic T. gondii contact were all IgG+ (44%; n=21) and exhibited increased plasma IL-33, IL-17A, and neuroserpin levels, but not CCL2, compared to uninfected pregnant women. Using Beck's depression inventory, we observed an increase in plasma IL-17A and IL-33 in women with T. gondii infeCction diagnosed with mild DS, whereas neuroserpin was associated with minor and moderate/severe DS. Our data suggest a close relationship between DS in pregnant women with chronic T. gondii infection and neurological conditions, which may be partially mediated by plasma neuroserpin, IL-33, and IL-17A levels.

Assessment of urine CCL2 as a potential diagnostic biomarker for acute kidney injury and septic acute kidney injury in intensive care unit patients

Acute kidney injury (AKI) is a prevalent and serious condition in the intensive care unit (ICU), associated with significant morbidity and mortality. Septic acute kidney injury (SAKI) contributes substantially to AKI cases in the ICU. However, current diagnostic methods have limitations, necessitating the exploration of novel biomarkers. In this study, we investigated the potential of plasma and urine CCL2 levels as diagnostic markers for AKI and SAKI in 216 ICU patients. Our findings revealed significant differences in plasma (p < 0.01) and urine CCL2 (p < 0.0001) levels between AKI and non-AKI patients in the ICU. Notably, urine CCL2 demonstrated promising predictive value for AKI, exhibiting high specificity and sensitivity (AUC = 0.8976; p < 0.0001). Furthermore, we observed higher urine CCL2 levels in SAKI compared to non-septic AKI (p < 0.001) and urine CCL2 could also differentiate SAKI from non-septic AKI (AUC = 0.7597; p < 0.0001). These results suggest that urine CCL2 levels hold promise as early biomarkers for AKI and SAKI, offering valuable insights for timely intervention and improved management of ICU patients.

Evaluation of plasma CCL3 levels in individuals with newly diagnosed chronic lymphocytic leukemia and it’s correlation with clinical and laboratory parameters

Abstract: BACKGROUND: The most prevalent type of leukemia in adults is called chronic lymphocytic leukemia (CLL). is a lymphoproliferative condition is defined by the mature clone’s expansion in blood, secondary lymphoid tissues, spleen and the bone marrow. CCL3 is a cytokine that is involved in development, repair, and the acute inflammatory state. CCL3, therefore, should become useful for risk assessment in patients with CLL. OBJECTIVES: The aims of the study were to estimate the level of plasma CCL3 in newly diagnosed patients with CLL matched to healthy controls and correlate it with hematological parameters and clinical parameters and prognostic markers such as CD38 and LAIR-1. PATIENTS, MATERIALS AND METHODS: This study was cross-sectional in nature. Patient group included 55 patients with newly established diagnosis of CLL proven by morphology and immunophenotyping and control group included sex and age matched of 30 healthy individuals. The plasma CCL3 levels were measured using an enzyme-linked immunosorbent assay. Microsoft Office Excel 2019 and SPSS version 26 were used for the statistical analysis. The mean and standard deviation of normally distributed numerical values whereas the terms “median” and “range” were used to describe numerical values that are not regularly distributed. P &lt;0.05 was used to determine the degree of significance. RESULTS: There were statistically significant relationships between CCL3 of patient (median level about 766.42 ng/ml) and control (median level about 453.35 ng/ml) groups (P &lt; 0.001). There was a strong correlation between CCL3 and white blood cell, hemoglobin, and absolute lymphocyte count (P = 0.013, P &lt; 0.001, and P = 0.011, respectively). There was a strong relationship between CCL3 expression with Binet stage and with hepatomegaly (P &lt; 0.001 and P = 0.020, respectively), but no significant relation between CCL3 expression and CD38 and LAIR-1. CONCLUSIONS: Patients with CLL had high levels of CCL3, which increased with advancing Binet stages. Therefore, our research clarified the useful and simplicity of measurement of CCL3 plasma levels for follow-up in CLL patients and risk assessment.

Abstract 15490: NIL10: A Novel Nanotechnological Compound to Prevent Monocyte Infiltration and Adverse Cardiac Remodeling in a Porcine Model of Myocardial Ischaemia-Reperfusion

Introduction: Adverse cardiac remodeling following acute myocardial infarction (AMI) depends on how promptly the phagocytic-nuclear system responds. Among strategies to limit the inflammatory response, we have developed a nanoparticle (NIL10) which binds to IL-10 receptor (IL-10R) in-vitro and promotes macrophage polarization towards a resolutive phenotype in animal models of myocardial ischemia-reperfusion (I/R). However, its therapeutic use still depends on understanding its ability to regulate monocyte recruitment. Hypothesis: Targeting the IL-10R in circulating monocytes may represent a new therapeutic approach to improve cardiac function in patients undergoing AMI. Objective: To explore the molecular mechanisms leading to the inhibition of monocyte recruitment by NIL10 in pigs undergoing cardiac I/R. Methods: By using a porcine model of myocardial I/R, we arranged the following groups: (1) control group (2) intravenous administration (IV) 1 mg/kg NIL10, (3) IV of 4x10 5 isolated monocytes from group 2, (4) IV of 4x10 5 isolated monocytes from group 1 and then incubated with NIL10 (A). Results: Groups 2-4 exhibited better cardiac function compared to group 1 (B), which resulted in a decrease in myocardial fibrosis (C), along with a reduction of circulating CCR2+ monocytes (D) and a decrease in classical-monocyte infiltration, as shown by a reduction of CCR2+ macrophages in the necrotic area of the heart (E). As a result, CCL2 plasma expression, a functional ligand of CCR2, was decreased by day 7 post-I/R (F) in contrast to the necrotic tissue expression profile in which we detected large amounts of CCL2 (G) and STAT3 activation, indicative of IL10R activity (H). Conclusion: In addition to macrophage polarization, NIL10 induces cardiac protection by limiting classical monocyte infiltration after myocardial I/R, which opens a new window for using, in combination with endogenous monocyte therapy, to treat AMI.

Collaborative plasma biomarkers for Parkinson's disease development and progression: a cross-sectional and longitudinal study.

Relying on a single biomarker for early diagnosis of Parkinson's Disease (PD) may not yield accurate results. We aimed to assess the combined diagnostic value of multiple biomarkers, including plasma CCL2, plasma CXCL12, and plasma neuronal exosomal α-synuclein (α-syn) for early-stage PD diagnosis and their predictive value in PD progression. This study included both cross-sectional and longitudinal designs. The CCL2, CXCL12, and neuronal exosomal α-syn levels were analyzed in 50 healthy controls (HCs) and 50 early-stage PD patients. Then, a prospective follow-up of 30 early-stage PD patients was performed. In early-stage PD, we observed a significant increase in CCL2, CXCL12, and plasma neuronal exosomal α-syn compared to HCs (P < 0.05). Utilizing a combined diagnostic approach of CCL2, CXCL12and α-syn significantly improved the area under the curve (AUC= 0.89, P < 0.001). Spearman correlation analysis revealed that CCL2 levels were correlated with PD clinical stage and autonomic symptoms (P < 0.05). CXCL12 levels were associated with non-motor symptoms (P < 0.05). Plasma neuronal exosome α-syn levels were connected to the clinical stage, motor symptoms, and non-motor symptoms in early-stage PD (P < 0.01). In the longitudinal cohort, the Cox regression analysis showed that high CCL2 levels were associated with motor progression after a mean follow-up of 24 months. Our study suggested that the combined measurement of plasma CCL2, CXCL12, and neuronal exosomal α-syn can improve early-stage PD diagnosis, and CCL2 may serve as a prognostic marker for PD progression.

CCL2 promotes lymphatic metastasis via activating RhoA and Rac1 pathway and predict prognosis to some extent in tongue cancer

ABSTRACT Background Oral tongue cancer is an extremely malignant tumor with high rate of lymphatic metastasis. Little is known about its invasion and metastasis mechanisms so far. Methods To clarify the main role of CCL2 in tongue cancer progression, we performed Transwell migration assay to confirm the effects of different concentrations of CCL2 on the migration and invasion of tongue cancer cells. Next, by siRNA interference of RhoA and Rac1 in LNMTca8113 cells, we are able to observe that these two molecules block the effect of CCL2 on cell migration and cytoskeleton reorganization by laser confocal microscopy. Moreover, the AKT phosphorylation level of PI3K downstream molecule under the action of CCL2 also be detected by qRT-PCR and western blot, so as to determine whether CCL2 affects the proliferation of LNMTca8113 cells through PI3K/AKT pathway. Finally, we analyzed the relationship between plasma CCL2 level and various clinicopathological parameters in patients with tongue cancer. Results: We found that tongue cancer cells treated with CCL2 migrate faster at first. CCL2 may enhance the invasion and migration of LNMTca8113 cells by activating RhoA and Rac1 to promote cytoskeleton reorganization. Promotion of LNMTca8113 migration induced by CCL2 was inhibited by silence of RhoA and Rac1. CCL2 could increase the phosphorylation of downstream Akt/PI3K signal and promoted the proliferation. Plasma concentration confirmed that the CCL2 level was closely related to the clinical stage of tongue cancer. Patients with lower CCL2 levels had a relatively longer progression-free survival and total survival time. Results After adding CCL2, the number of proliferation and migration of tongue cancer cells increased and the expression of RhoA and Rac1 rose up in LNMTca8113 cell line. The cytoskeleton reorganization was notable. Patients with higher serum levels of CCL2 had shorter progression-free survival than those with lower levels of CCL2 (P < 0.0001). Conclusions CCL2 promotes the invasion and metastasis of tongue cancer by PI3K/Akt pathway. The plasma level of CCL2 may predict prognosis of tongue cancer patients. CCL2 can serve as a potential therapeutic target for tongue cancer treatment.

Interstitial lung disease and mycobacteriosis in children with inherited CCR2 deficiency

Tissue-resident alveolar macrophages are important for lung homeostasis and innate immunity. They originate from fetal monocytes and are maintained in the lung through self-renewal or may arise from recruited circulating monocytes. Disturbance of alveolar macrophage function, their numbers or loss of GM-CSF signaling can all underlie pulmonary alveolar proteinosis (PAP). Here, we report eight patients (aged 8–21 years) from four kindreds and three ancestries suffering from recurrent pneumonia, progressive interstitial fibrosis, and PAP. All patients are deficient for the monocyte-chemoattractant protein-1 (CCL-2) receptor 2 (CCR2). Five patients are homozygous and three are compound heterozygous for private or rare CCR2 variants. The variants are loss-of-function for Ca2 +-release and cell migration upon CCL-2 stimulation, when tested by overexpression in monocytic THP-1 cells. Moreover, CCL-2-dependent migration and Ca2+-release of the patients’ monocytes are abolished, while their plasma CCL-2 levels are elevated. Yet, CCR2-deficient cells respond normally to GM-CSF. In addition, the counts, frequencies, and transcriptomes of blood lymphoid and myeloid subsets are normal. Mice deficient for CCR2 display alveolar septal wall thickening and increased number of alveolar type II cells producing surfactant protein C causing increased lung tissue hysteresis. CCR2-deficient mice are vulnerable to mycobacteria, with impaired attraction of blood monocytes to infected tissues. These findings suggest that human CCR2 is essential for the recruitment of monocytes to both pulmonary alveoli and tissues infected with mycobacteria.

Association of elevated plasma CCL5 levels with high risk for tic disorders in children.

This study identifies associations of a set of circulating cytokines, particularly CCL5 with TD development, and provides evidence that high blood CCL5 has potential to be a risk factor for TD development. identifier ChiCTR-2000029616.

Plasma Markers for Early Prediction of Radiation-Induced Myocardial Damage.

There is no sensitive and effective method to predict radiation-induced myocardial damage (RIMD). The aim of this study was to explore effective plasma biomarkers for early prediction of RIMD after radiotherapy (RT) in lung cancer patients and in a rat model. Biomarker levels were measured in plasma samples collected before and after thoracic RT from 17 lung cancer patients. For the animal model, a single radiation dose of 40 Gy was delivered to the cardiac apex of female Wistar rats. Control rats received sham irradiation (0 Gy). Dynamic plasma biomarker detection and histopathological analysis to confirm RIMD were performed in rats up to 6 months after RT. In lung cancer patients, the plasma caspase-3 concentration was significantly increased after thoracic RT (P = 0.0479), with increasing but nonsignificant trends observed for caspase-1, CCL2, vascular endothelial growth factor (VEGF), interleukin-1β, and IL-6 (P > 0.05). Changes in caspase-3, VEGF, and IL-6 correlated significantly with mean heart dose (P < 0.05). In the RIMD rat model, caspase-1, caspase-3, CCl-2, VEGF, CCl-5, and TGF-β1 levels were significantly elevated in the first week post-RT (P < 0.05), which was earlier than pathological changes. Myocardial tissue of the RIMD rats also showed significant macrophage infiltration at 1 month (P < 0.01) and fibrosis at 6 months postradiation (P < 0.0001). Macrophage infiltration correlated significantly with plasma caspase-3, CCL2, CCL5, VEGF, and TGF-β1 levels from 3 weeks to 2 months post-RT. Increased plasma caspase-1, caspase-3, CCl-2, and VEGF levels were detected before RIMD-related pathological changes, indicating their clinical potential as biomarkers for early prediction of RIMD.

Hepatic stellate cell activation markers are regulated by the vagus nerve in systemic inflammation

BackgroundThe liver is an important immunological organ and liver inflammation is part of the pathophysiology of non-alcoholic steatohepatitis, a condition that may promote cirrhosis, liver cancer, liver failure, and cardiovascular disease. Despite dense innervation of the liver parenchyma, little is known about neural regulation of liver function in inflammation. Here, we study vagus nerve control of the liver response to acute inflammation.MethodsMale C57BL/6 J mice were subjected to either sham surgery, surgical vagotomy, or electrical vagus nerve stimulation followed by intraperitoneal injection of the TLR2 agonist zymosan. Animals were euthanized and tissues collected 12 h after injection. Samples were analyzed by qPCR, RNAseq, flow cytometry, or ELISA.ResultsHepatic mRNA levels of pro-inflammatory mediators Ccl2, Il-1β, and Tnf-α were significantly higher in vagotomized mice compared with mice subjected to sham surgery. Differences in liver Ccl2 levels between treatment groups were largely reflected in the plasma chemokine (C–C motif) ligand 2 (CCL2) concentration. In line with this, we observed a higher number of macrophages in the livers of vagotomized mice compared with sham as measured by flow cytometry. In mice subjected to electrical vagus nerve stimulation, hepatic mRNA levels of Ccl2, Il1β, and Tnf-α, and plasma CCL2 levels, were significantly lower compared with sham. Interestingly, RNAseq revealed that a key activation marker for hepatic stellate cells (HSC), Pnpla3, was the most significantly differentially expressed gene between vagotomized and sham mice. Of note, several HSC-activation associated transcripts were higher in vagotomized mice, suggesting that signals in the vagus nerve contribute to HSC activation. In support of this, we observed significantly higher number of activated HSCs in vagotomized mice as compared with sham as measured by flow cytometry.ConclusionsSignals in the cervical vagus nerve controlled hepatic inflammation and markers of HSC activation in zymosan-induced peritonitis.

CCL3 and CCL5 as potential markers of carotid atherosclerotic plaque stability – preliminary research

Introduction: Carotid atherosclerosis is one of the main causes of ischaemic stroke. The study verified the hypothesis on the relationship between the expression of selected inflammatory markers and the stability of atherosclerotic plaque in stroke patients. Aim: The aim of the study was to determine CCL3 and CCL5 levels in both plasma and carotid atherosclerotic plaques in relation to the history of ischaemic stroke, as well as to assess plaque morphology and stability. Materials and methods: The levels of CCL3 and CCL5 chemokines were determined by ELISA for both plasma and supernatants of atherosclerotic plaque homogenates from patients undergoing endarterectomy due to at least 70% carotid artery stenosis. Results: Both chemokines were found in atherosclerotic plaques, with elevated CCL3 in unstable plaques. Furthermore, patients with atherosclerosis showed significantly higher plasma CCL5 compared to healthy individuals. Conclusions: The chemokines CCL3 and CCL5 are likely to be involved in the inflammatory processes contributing to the development of atherosclerotic plaque, but this needs to be confirmed in further studies.

Dynamics of CXCR4 positive circulating tumor cells in prostate cancer patients during radiotherapy.

Ablative radiotherapy is a highly efficient treatment modality for patients with metastatic prostate cancer (PCa). However, a subset of patients does not respond. Currently, this subgroup with bad prognosis cannot be identified before disease progression. We hypothesize that markers indicative of radioresistance, stemness and/or bone tropism may have a prognostic potential to identify patients profiting from metastases-directed radiotherapy. Therefore, circulating tumor cells (CTCs) were analyzed in patients with metastatic PCa (n=24) during radiotherapy with CellSearch, multicolor flow cytometry and imaging cytometry. Analysis of copy-number alteration indicates a polyclonal CTC population that changes after radiotherapy. CTCs were found in 8 out of 24 patients (33.3%) and were associated with a shorter time to biochemical progression after radiotherapy. Whereas the total CTC count dropped after radiotherapy, a chemokine receptor CXCR4-expressing subpopulation representing 28.6% of the total CTC population remained stable up to 3 months. At once, we observed higher chemokine CCL2 plasma concentrations and proinflammatory monocytes. Additional functional analyses demonstrated key roles of CXCR4 and CCL2 for cellular radiosensitivity, tumorigenicity and stem-like potential in vitro and in vivo. Moreover, a high CXCR4 and CCL2 expression was found in bone metastasis biopsies of PCa patients. In summary, panCK+ CXCR4+ CTCs may have a prognostic potential in patients with metastatic PCa treated with metastasis-directed radiotherapy.

The association between plasma chemokines and breast cancer risk and prognosis: A mendelian randomization study.

Background: Despite the potential role of several chemokines in the migration of cytotoxic immune cells to prohibit breast cancer cell proliferation, a comprehensive view of chemokines and the risk and prognosis of breast cancer is scarce, and little is known about their causal associations. Methods: With a two-sample Mendelian randomization (MR) approach, genetic instruments associated with 30 plasma chemokines were created. Their genetic associations with breast cancer and its survival by molecular subtypes were extracted from the recent genome-wide association study of 133,384 breast cancer cases and 113,789 controls, with available survival information for 96,661 patients. We further tested the associations between the polygenic risk score (PRS) for chemokines and breast cancer in the UK Biobank cohort using logistic regression models, while the association with breast cancer survival was tested using Cox regression models. In addition, the association between chemokine expression in tumors and breast cancer survival was also analyzed in the TCGA cohort using Cox regression models. Results: Plasma CCL5 was causally associated with breast cancer in the MR analysis, which was significant in the luminal and HER-2 enriched subtypes and further confirmed using PRS analysis (OR = 0.94, 95% CI = 0.89-1.00). A potential causal association with breast cancer survival was only found for plasma CCL19, especially for ER-positive patients. Although not replicated in the UK Biobank, we still found an inverse association between CCL19 expression in tumors and breast cancer overall and relapse-free survival in the TCGA cohort (HR = 0.58, 95% CI = 0.35-0.95). Conclusion: We observed an inverse association between genetic predisposition to CCL5 and breast cancer, while CCL19 was associated with breast cancer survival. These associations suggested the potential of these chemokines as tools for breast cancer prevention and treatment.

Circulating VEGF-A, TNF-α, CCL2, IL-6, and IFN-γ as biomarkers of cancer in cancer-associated anti-TIF1-γ antibody-positive dermatomyositis

ObjectivesThe objective of the current study was to detect plasma profiles of inflammatory cytokines for determining potential biomarkers indicating cancer presence among the anti-TIF1-γ antibody-positive dermatomyositis (DM) patients.MethodsTwenty-seven cancer-associated anti-TIF1-γ antibody-positive DM (Cancer TIF1-γ-DM) patients were compared with 20 anti-TIF1-γ antibody-positive DM patients without cancer (Non-cancer TIF1-γ-DM) and 10 healthy controls (HC). The plasma levels of 17 cytokines were determined using the Luminex 200 system. The ability of plasma VEGF-A, TNF-α, CCL2, IL-6, and IFN-γ levels to distinguish the presence of cancer was evaluated through the area under the curve (AUC) analysis. Potential protein interactions of TIF1-γ and the five cytokines were analyzed using the STRING database.ResultsVEGF-A, TNF-α, CCL2, IL-6, and IFN-γ plasma levels were significantly higher in the Cancer TIF1-γ-DM group, especially those without any anticancer treatment, than those in the non-cancer TIF1-γ-DM and HC groups. Meanwhile, anti-TIF1-γ antibody and the five cytokines could distinguish cancer presence in anti-TIF1-γ antibody-positive DM patients. The STRING network indicated that TIF1-γ potentially interacted with the cytokines. Positive correlations of VEGF-A among CCL2, IL-6, and IFN-γ and between IFN-γ and IL-6 were observed in Cancer TIF1-γ-DM patients. VEGF-A, TNF-α, CCL2, and IL-6 were positively associated with muscle-associated enzymes among the Cancer TIF1-γ-DM patients.ConclusionThe present study identified VEGF-A, TNF-α, CCL2, IL-6, and IFN-γ as significant potential biomarkers indicating the presence of cancer and demonstrated a more detailed cytokine profile during diagnosis. These biomarkers could provide better screening strategies and insight into the Cancer TIF1-γ-DM pathogenesis.Key Points• VEGF-A, TNF-α, CCL2, IL-6, and IFN-γ are potential biomarkers of cancer in cancer-associated anti-TIF1-γ antibody-positive dermatomyositis.Graphical abstractPotential pathogenic molecular mechanism of the cancer-associated anti-TIF1-γ antibody-positive dermatomyositis

Immunomodulatory effect of first-in-human PeriCord cardiac bioimplant: preliminary data of the PERISCOPE clinical trial

Abstract Background The PERISCOPE is a first-in-human, phase I, double blind, one centre clinical trial to test the safety of the PeriCord, an advanced therapy medicinal product (PEI18–140), for the treatment of patients with infarcted myocardial tissue. The PeriCord is a GMP-complying allogeneic engineered tissue graft consisting on a decellularised pericardial matrix colonised with umbilical cord Wharton's jelly mesenchymal stromal cells. The PeriCord implantation has shown to promote damaged tissue revascularisation, reduce infarct size, adverse remodelling and fibrosis, and ultimately improve cardiac function preclinically. Purpose To assess the safety and monitor the monocyte and cytokine response after PeriCord implantation in patients with infarcted myocardial tissue. Methods The PERISCOPE clinical trial has been approved by AEMPS and the Local Ethics Committee of our institution (Eudra-CT 2018–001964–49). Twelve patients with transmural myocardial infarction (&amp;gt;50% by MRI) who were candidates for surgical revascularisation were included: two roll-in and 10 randomised into a Control group (n=5; CABG) or Treatment group (n=5; n=7 in total; CABG and PeriCord implantation over the transmural myocardial scar). In conjunction with clinical follow-up, whole blood was sampled at baseline and 3-, 6-, and 9-days post-surgery for monocyte populations analysis by flow cytometry and plasma cytokine and monocyte chemoattractant chemokine levels by multiplex ELISA. Results The target patient enrolment has been met and no adverse effects related to PeriCord implantation were observed so far. Recruitment of CCR2+ activated monocytes in peripheral blood peaked on day 3 post-surgery in both groups (increase in the %CCR2+ monocytes of 6.1±5.7% in Control, p=0.38; and 6.5±1.8% in PeriCord Treated patients, p=0.0004), concomitant with a surge in the monocyte chemoattractant CCL2 plasma levels. At the same time, there was a decrease in the number of “non-classical” monocytes regardless of treatment (decrease in CD14-/CD16+ monocytes of 16.7±11.1% in Control, p&amp;lt;0.01; and 24.0±15.0% in PeriCord Treated patients, p&amp;lt;0.001) and a marked reduction in CX3CR1 expression in monocytes of PeriCord treated patients (decrease of 53.2±20.6% in mean fluorescence intensity at day 3, p&amp;lt;0.01), while plasma CX3CL1 levels were undetectable. Both populations recovered on day 9 only in treated patients (p&amp;lt;0.05). Conclusions Implantation of the PeriCord in myocardial infarction patients did not promote adverse reactions and modulated circulating monocyte subsets that have been associated with post-infarction myocardial tissue healing (CCR2 and CX3CR1). These results will be analysed for correlation with therapeutic benefits by the end of patient follow-up. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto Carlos III, Generalitat de Catalunya

The Relationship between CC Ligand 5 Plasma Levels and Modic Changes in Low Back Pain Patients’ Severity

Background: Low back pain (LBP) is one of the global health problems. The most common cause of LBP is disc degeneration. Modic changes (MC) are the most common MRI features in patients with disc degeneration. As a result of cartilage and disc tissue damage, CCL 5 is released and modulates pain responses in the dorsal root ganglion. This study aims to determine the relationship between CCL5 levels and the description of Modic changes on MRI with pain levels in patients with low back pain.&#x0D; Methods: This study is a cross-sectional study. The research subjects were LBP patients who were treated at the Neurology Polyclinic, Dr. M. Djamil General Hospital, Padang, in the range of March 2021-December 2021, who meets the inclusion and exclusion criteria. Subjects will be taken blood to assess CCL5 plasma levels, pain assessment using the McGill Pain Questionnaire, and undergo an MRI examination.&#x0D; Results: A total of 52 subjects consisted of 23 men and 29 women with an age range of 34-77 years. Most of the Modic changes were found in the type 2 group. Based on the pain scale, there were two groups with mild pain and moderate pain. On examination of plasma CCL 5 levels, the median value of plasma CCL5 levels was 303,271 ng/L. There was a significant relationship between plasma CCL5 levels and pain levels in patients with low back pain (p = 0.004). There was no significant relationship between Modic changes and the severity of pain.&#x0D; Conclusion: Plasma CCL5 levels are associated with pain levels in patients with low back pain, while Modic changes are not associated with pain severity.

Chromogranin A plays a crucial role in age‐related development of insulin resistance and hypertension

ObjectiveAging is a public health, societal, and economic problem around the world. Adults aged 65 years and older are the fastest growing segment of the US population, and their number is expected to double to 89 million by 2050. Two physiological processes that are more prevalent in older populations are hypertension and diabetes. Chromogranin A (protein: CgA; mouse gene: Chga) knockout (Chga‐KO) mice are associated with hypertension but also protected against developing autoimmune diabetes; however, the effect of these phenotypes on mice as they age including mortality remains unclear, as does a possible mechanism for developing both phenotypes. This study examined the long‐term effects of aging in Chga‐KO mice and sought to elucidate a possible mechanism for both hypertension and diabetes by focusing on the inflammatory pathway.Methods and ResultsChga‐KO mice display two opposite aging phenotypes: hypertension but heightened insulin sensitivity. We determined these phenotypes in aging CgA mice by measuring blood pressure and blood glucose. In comparison, aging wild‐type (WT) mice gradually lost glucose tolerance and insulin sensitivity. Moreover, while aging WT mice had increased inflammation with higher plasma TNF‐a, IFN‐g and CCL2 and increased mitochondrial fission, these phenotypes were the opposite in aging Chga‐KO mice. Chga‐KO mice also showed increased expression of mitochondrial and nuclear‐encoded complex I genes, implying that they were healthier than WT mice. Most intriguingly, the hypertension in Chga‐KO mice spontaneously reversed with aging. Supplementation of Chga‐KO mice with pancreastatin (human CgA273‐301), a hyperglycemic peptide produced from CgA by proteolysis, increased both blood glucose levels and blood pressure, implicating hyperglycemia, and hypertension.ConclusionsWe conclude that age‐related insulin resistance and hypertension are caused in part by CgA.

Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy.

The central nervous system (CNS) HIV reservoir is an obstacle to achieving an HIV cure. The basal ganglia harbor a higher frequency of SIV than other brain regions in the SIV-infected rhesus macaques of Chinese-origin (chRMs) even on suppressive combination antiretroviral therapy (ART). Since residual HIV/SIV reservoir is associated with inflammation, we characterized the neuroinflammation by gene expression and systemic levels of inflammatory molecules in healthy controls and SIV-infected chRMs with or without ART. CCL2, IL-6, and IFN-γ were significantly reduced in the cerebrospinal fluid (CSF) of animals receiving ART. Moreover, there was a correlation between levels of CCL2 in plasma and CSF, suggesting the potential use of plasma CCL2 as a neuroinflammation biomarker. With higher SIV frequency, the basal ganglia of untreated SIV-infected chRMs showed an upregulation of secreted phosphoprotein 1 (SPP1), which could be an indicator of ongoing neuroinflammation. While ART greatly reduced neuroinflammation in general, proinflammatory genes, such as IL-9, were still significantly upregulated. These results expand our understanding of neuroinflammation and signaling in SIV-infected chRMs on ART, an excellent model to study HIV/SIV persistence in the CNS.

Plasma C-C Chemokine Concentrations in Intermediate Age-Related Macular Degeneration.

Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration.Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups.Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls.Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.