Inflammatory Chemokine Receptors Research Articles

Investigating the potential mechanism of Pioglitazone in Sepsis-Related brain injury through transcriptomics

Sepsis-related brain injury (SRBI) refers to brain dysfunction and structural damage caused by sepsis, which is characterized by inflammation, oxidative stress, and destruction of the blood–brain barrier. Pioglitazone is a PPAR-γ agonist in which PPAR-γ acts as an inflammatory modulator, determining the relationship between PPAR-γ and SRBI and inflammatory state is critical for the disease. This study aimed to construct a drug-target-disease network for SRBI and Pioglitazone based on network pharmacology, and to investigate the therapeutic effect and potential mechanism of Pioglitazone in SRBI induced by lipopolysaccharide (LPS) in rats through transcriptomics. To establish a rat Model of SRBI by intraperitoneal injection of LPS (10 mg/kg): SD rats were divided into Control, Model (LPS), Pioglitazone, (LPS + Pioglitazone) and GW9662 group (LPS+GW9662). The effects and potential mechanisms of Pioglitazone in the treatment of SRBI were studied using biochemical indexes, pathological changes and transcriptome-sequencing (RNA-seq). RNA-seq results showed 620 DEGs between the Model and the Pioglitazone groups. Enrichment analysis involved multiple inflammatory response processes and chemokine receptor binding functions. TLR4 and CXCL10 in the Toll signaling pathway may play an important role in SRBI as important targets. Pioglitazone may ameliorate SRBI through the PPAR-γ/TLR4/CXCL10 pathway.

CCR1 and CCR2 Coexpression on Monocytes Is Nonredundant and Delineates a Distinct Monocyte Subpopulation.

The interactions between chemokines and their receptors, particularly in the context of inflammation, are complex, with individual receptors binding multiple ligands and individual ligands interacting with multiple receptors. In addition, there are numerous reports of simultaneous coexpression of multiple inflammatory chemokine receptors on individual inflammatory leukocyte subtypes. Overall, this has previously been interpreted as redundancy and proposed as a protective mechanism to ensure that the inflammatory response is robust. By contrast, we have hypothesized that the system is not redundant but exquisitely subtle. Our interests relate to the receptors CCR1, CCR2, CCR3, and CCR5, which, together, regulate nonneutrophilic myeloid cell recruitment to inflammatory sites. In this study, we demonstrate that although most murine monocytes exclusively express CCR2, there is a small subpopulation that is expanded during inflammation and coexpresses CCR1 and CCR2. Combinations of transcript and functional analysis demonstrate that this is not redundant expression and that coexpression of CCR1 and CCR2 marks a phenotypically distinct population of monocytes characterized by expression of genes otherwise typically associated with neutrophils. Single-cell RNA sequencing confirms this as a monodisperse population of atypical monocytes. This monocytic population has previously been described as having immunosuppressive activity. Overall, our data confirm combinatorial chemokine receptor expression by a subpopulation of monocytes but demonstrate that this is not redundant expression and marks a discrete monocytic population.

Patients with ankylosing spondylitis present a distinct CD8 T cell subset with osteogenic and cytotoxic potential

ObjectivesAnkylosing spondylitis (AS) is a chronic inflammatory rheumatic disease affecting mainly the axial skeleton. Peripheral involvement (arthritis, enthesitis and dactylitis) and extra-musculoskeletal manifestations, including uveitis, psoriasis and bowel inflammation, occur...

Adhesion G Protein-Coupled Receptor G2 Promotes Hepatocellular Carcinoma Progression and Serves as a Neutrophil-Related Prognostic Biomarker.

Adhesion G protein-coupled receptor G2 (ADGRG2) is an orphan adhesion G protein-coupled receptor (GPCR), which performs a tumor-promoting role in certain cancers; however, it has not been systematically investigated in hepatocellular carcinoma (HCC). In the current study, we utilized multiple databases to analyze the expression and diagnostic and prognostic value of ADGRG2 in HCC and its correlation with immune infiltration and inflammatory factors. The function and upstream regulatory miRNA of ADGRG2 were validated through qPCR, Western blot, CCK8, wound healing, and dual luciferase assays. It turned out that ADGRG2 was significantly higher in HCC and had a poor survival rate, especially in AFP ≤ 400 ng/mL subgroups. Functional enrichment analysis suggested that ADGRG2 may be involved in cancer pathways and immune-related pathways. In vitro, siRNA-mediated ADGRG2 silencing could inhibit the proliferation and migration of Huh7 and HepG2 cells. There was a highly significant positive correlation between ADGRG2 and neutrophils. Moreover, NET-related genes were filtered and confirmed, such as ENO1 and S100A9. Meanwhile, the high expression of ADGRG2 was also accompanied by the highest number of inflammatory cytokines, chemokines, and chemokine receptors and good immunotherapy efficacy. Finally, AGDGR2 may be sensitive to two drugs (PIK-93 and NPK76-II-72-1) and can be targeted by miR-326. In conclusion, ADGRG2 may serve as a novel biomarker and drug target for HCC diagnosis, immunotherapy, and prognosis and was related to neutrophils and the inflammatory process of liver cancer development.

Naive CD4 T Cells Highly Expressing the Inflammatory Chemokine Receptor CXCR3 Increase with Age and Radiation Exposure in Atomic Bomb Survivors.

The numbers of naive T cells that react to novel pathogens not yet encountered by an immune system, decrease during aging, mainly due to age-associated involution of the thymus. CD45RA+ naive CD4 T cells consist of heterogeneous populations, including highly CXCR3-expressing cells that appear during the homeostatic proliferation of naive T cells and exhibit enhanced type-1 inflammatory phenotypes. Based on previous evidence of radiation-associated reductions in thymic function and peripheral blood naive CD4 T cells, we hypothesized that the homeostatic proliferation of naive CD4 T cells compensates for deficits in peripheral T-cell populations after radiation injury, which may increase the proportion of CXCR3high cells in naive CD4 T cells and enhance inflammation. The statistical models employed in this study revealed positive associations between the number of CXCR3high naive CD4 T cells and age as well as radiation dose among 580 Hiroshima atomic bomb survivors. In addition, the CXCR3high cells in these survivors increased not only with the levels of homeostatic cytokines, IL6 and IL7, but also with those of inflammatory indicators, CXCL10 and CRP. These results suggest that thymic T-cell production deficiency due to radiation and aging results in enhanced homeostatic proliferation that drives the appearance of CXCR3high naive CD4 T cells poised for an inflammatory response. Molecular mechanisms and clinical relevance of increasing CXCR3high cells in naive CD4 T populations should be further investigated in the context of inflammatory disease development long after radiation exposure.

Global deficiency in the inflammatory chemokine receptors 1,2,3 and 5 ameliorates atherosclerosis and selectively modulates aortic myeloid cell phenotype

Abstract Background Atherosclerosis is a chronic inflammatory disease in which leukocytes traffic to the vessel wall, a process in part mediated by the inflammatory chemokine receptors (iCCRs): Ccr1, Ccr2, Ccr3 and Ccr5. ICCRs display significant ligand promiscuity and redundancy, which have hampered the definitive deduction of the isolated and collective roles of these receptors. Purpose To assess iCCR expression in human and mouse atherosclerosis and determine the contribution of global iCCR expression to atherosclerosis formation in mice. Methods We derived data from the human carotid endarterectomy biobanks, Athero-Express and Biobank of Karolinska Endarterectomy (BiKE) to investigate iCCR expression. Next, we employed fluorescent reporter mice (iREP) to track iCCR expression via flow cytometry and confocal microscopy. To ascertain the contribution of iCCRs to atherosclerosis, we utilised mice in which the complete iCcr locus incorporating Ccr1, Ccr2, Ccr3 and Ccr5 has been deleted (TACKO mice). We induced atherosclerosis using tail vein injection of AAV8- proprotein convertase subtilisin/kexin type 9 (PCSK9) in combination with 12- or 20-weeks Western diet (WD). Plaque size and composition was assessed via histology while cytometry of time-of-flight (CyTOF) and single-cell RNA-sequencing (scRNA-seq) were used to assess cellular changes. Results By analysing scRNA-seq data from Athero-Express, CCR1 emerged as the most strongly expressed iCCR and was highly localised to macrophages. Next, by utilizing BiKE data, we discovered that CCR1, 2 and 5 expression increased in plaques compared to healthy vessels, with CCR1 and CCR5 more strongly associated with symptomatic patients compared with asymptomatic patients. In iREP mice, CCR1, 2 and 5+ cell numbers were significantly increased in the atherosclerotic aorta compared with healthy mice. Cellular expression levels were variable with CCR2 being dominant in the plaque and increasing markedly on macrophages. Following 12 weeks WD, there was a reduction in mean plaque area within the aortic sinus of TACKO mice (WT 0.20 mm² vs. TACKO 0.10 mm², n=19-20, P<0.0001). Following 20 weeks WD, mean plaque area was also reduced in TACKO mice (WT 0.41 mm² vs. TACKO 0.25 mm², n=9-12, P<0.01) and this was associated with a significant reduction in necrotic core area and a reduction in calcification, reflecting a shift towards a more stable plaque phenotype, as classified according to the Virmani grading system. CyTOF analysis revealed reductions in inflammatory monocytes and conventional type 2 dendritic cells in TACKO aorta accompanied by a phenotypic switch in macrophages towards a less inflammatory phenotype. Finally, scRNA-seq analysis revealed phenotypic differences in non-immune vascular cells between WT and TACKO mice. Conclusion Our results support an athero-protective, plaque-stabilizing effect of iCcr deletion with a selective reduction in inflammatory myeloid cell aortic homing.

SATB1 is a master gatekeeper that limits virus-specific CD8 +T cell differentiation.

Abstract Special AT-rich sequence binding protein-1 (SATB1) is a chromatin binding protein that has key roles in ensuring appropriate chromatin structure and remodelling during T cell development. While a role for SATB1 in both CD4 +T regulatory and CD4 +T H2 lineage specific function has been described, little is known about its role during virus-specific CD8 +T cell differentiation. Here we demonstrate that SATB1 down regulation is associated with naïve CD8 +T cell activation and subsequent differentiation. Genome wide SATB1 binding indicates that SATB1 is critical for maintaining the naïve CD8 +T cell transcriptional programs prior to activation. Overexpression of SATB1 upon CD8 +T cell activation results in major restraint of virus-specific CD8 +cell differentiation resulting in lower expression of inflammatory chemokine receptors, checkpoint molecules such as PD-1 and limits effector CD8 +T cell infiltration into infected tissues. Moreover, SATB1 over expression maintains high levels of TCF-1 expression and maintenance of the naïve T cell program. Our data suggest that SATB1 expression within naïve CD8 +T cells acts as gatekeeper for maintaining the naïve T cell program, and that down regulation upon activation is required for optimal effector CD8 +T cell differentiation. Supported by grants from the Australian Research Council (DP170102020).

Chemokine receptors in GtoPdb v.2023.1

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [438, 437, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibacterials, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [693] and aliases.

Blocking activation of CD4−CD8− T cells modulates their cytotoxic potential and decreases the expression of inflammatory and chemotactic receptors

CD4−CD8− (double negative – DN) T cells represent a small fraction of circulating T lymphocytes but are a major source of pro-inflammatory cytokines in patients with infectious diseases, including chronic Chagas cardiomyopathy (CCC), one of the deadliest cardiopathies known. Chagas disease is caused by an infection with the protozoan parasite Trypanosoma cruzi and can lead to either an asymptomatic form or a high-mortality cardiac disease. While circulating DN T cells represent a major inflammatory cytokine-expressing cell population in Chagas disease, their potential to be recruited to the heart and to perform cytotoxicity has not been determined. Our previous studies showed that blocking DN T cell activation decreases the expression of IFN-gamma, a cytokine involved in the severity of CCC. Here, studying a well-characterized cohort of Chagas patients with CCC or the asymptomatic form of Chagas disease (indeterminate form, IND), we evaluated the expression of cytotoxic molecules, cytokine and chemokine receptors in γδ+ and αβ+ DN T cells by multiparameter flow cytometry, and investigated whether blocking the activation of DN T cells influences the expression of these molecules. We observed that DN T cells from CCC display a higher expression of granzyme A, perforin, inflammatory molecules, and inflammatory chemokine receptors than cells from IND. Messenger RNA coding for these molecules is also upregulated in the heart of CCC patients. Importantly, blocking the activation of DN T cells from CCC modulates their cytotoxic potential and the expression of inflammatory and of chemokine receptors, suggesting that targeting DN T cell activation may be a valid strategy to reduce recruitment to the heart, inflammation, cytotoxicity and, thereby diminish CCC progression and severity.

CD103+ Cells and Chemokine Receptor Expression in Breast Cancer.

Mucosal environments harbour lymphocytes, which express several adhesion molecules, including intestinal homing receptors and integrin αE/β7 (CD103). CD103 binds E-cadherin, an integrin receptor expressed in intestinal endothelial cells. Its expression not only enables homing or retention of T lymphocytes at these sites but is also associated with increased T lymphocyte activation. However, it is not yet clear how CD103 expression is related to the clinical staging of breast cancer, which is determined by factors such as the size of the tumor (T), the involvement of nearby lymph nodes (N), and presence of metastasis (M). We examined the prognostic significance of CD103 by FACS in 53 breast cancer patients and 46 healthy controls enrolled, and investigated its expression, which contributes to lymphocyte recruitment in tumor tissue. Patients with breast cancer showed increased frequencies of CD103+, CD4+CD103+, and CD8+CD103+ cells compared to controls. CD103 was expressed at a high level on the surfaces of tumor-infiltrating lymphocytes in patients with breast cancer. Its expression in peripheral blood was not correlated with clinical TNM stage. To determine the localisation of CD103+ cells in breast tissue, tissue sections of breast tumors were stained for CD103. In tissue sections of breast tumors stained for CD103, its expression in T lymphocytes was higher compared to normal breast tissue. In addition, CD103+ cells expressed higher levels of receptors for inflammatory chemokines, compared to CD103- cells. CD103+ cells in peripheral blood and tumor tissue might be an important source of tumor-infiltrating lymphocyte trafficking, homing, and retention in cancer patients.

Single-Cell Transcriptomics Reveals Discrete Steps in Regulatory T Cell Development in the Human Thymus.

CD4+CD25+FOXP3+ regulatory T (Treg) cells control immunological tolerance. Treg cells are generated in the thymus (tTreg) or in the periphery. Their superior lineage fidelity makes tTregs the preferred cell type for adoptive cell therapy (ACT). How human tTreg cells develop is incompletely understood. By combining single-cell transcriptomics and flow cytometry, we in this study delineated three major Treg developmental stages in the human thymus. At the first stage, which we propose to name pre-Treg I, cells still express lineage-inappropriate genes and exhibit signs of TCR signaling, presumably reflecting recognition of self-antigen. The subsequent pre-Treg II stage is marked by the sharp appearance of transcription factor FOXO1 and features induction of KLF2 and CCR7, in apparent preparation for thymic exit. The pre-Treg II stage can further be refined based on the sequential acquisition of surface markers CD31 and GPA33. The expression of CD45RA, finally, completes the phenotype also found on mature recent thymic emigrant Treg cells. Remarkably, the thymus contains a substantial fraction of recirculating mature effector Treg cells, distinguishable by expression of inflammatory chemokine receptors and absence of CCR7. The developmental origin of these cells is unclear and warrants caution when using thymic tissue as a source of stable cells for ACT. We show that cells in the major developmental stages can be distinguished using the surface markers CD1a, CD27, CCR7, and CD39, allowing for their viable isolation. These insights help identify fully mature tTreg cells for ACT and can serve as a basis for further mechanistic studies into tTreg development.

Native Low-Density Lipoproteins Act in Synergy with Lipopolysaccharide to Alter the Balance of Human Monocyte Subsets and Their Ability to Produce IL-1 Beta, CCR2, and CX3CR1 In Vitro and In Vivo: Implications in Atherogenesis.

Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 μg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli’s atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis.

Conjugated Bile Acids Activate Lymphangiogenic Pathways, Induce Chemokine Production and Significantly Alter Cellular Metabolism in Lymphatic Endothelial Cells

Elevated levels of conjugated bile acids (BA) such as taurochenodeoxycholic acid (TCDCA) and taurocholic acid (TCA) are found in serum of patients with chronic inflammatory liver diseases and liver cancers. Increased lymphangiogenesis has been documented in several chronic liver diseases, as lymphatics are integral to the hepatic microcirculation and also plays an important role in early metastasis of liver cancers like hepatocellular and cholangiocarcinoma. High levels of BAs have been shown in metastatic tumor-bearing LNs compared to naive LNs, however, the effects of BAs on lymphatic endothelial cells (LECs) remain completely undefined. The present study focuses on investigating the effects of TCDCA and TCA on inducing molecular and metabolic changes in LECs. LECs were treated with TCDCA (100 uM) and TCA (100 uM) for 24hrs in presence or absence of specific BA receptor inhibitor (FXR or TGR5: 50uM) and the changes in proliferation, migration, tube formation was determined. Effects of BAs on LEC cellular metabolism was assessed by Seahorse analysis and lactate levels, ATP production and ROS was measured by fluorometric assays. mRNA levels of bile acid receptors- FXR, TGR5, VDR as well as receptors for VEGF and FGF, chemokines and chemokine receptors were analyzed by real time quantitative PCR. Inhibitor for TGR5 was used to test the role of TGR5. Our results showed that LECs express the BA receptors FXR, TGR5 and VDR with TGR5 showing highest basal level expression. Both TCDCA and TCA induced significant induction in migration rates as well as increased LEC tube formation. Among the two BA used, TCDCA induced more metabolic changes in LECs than TCA with significant increase in maximal glycolytic capacity as well as basal rate of ATP production. These alterations were abrogated in presence of the TGR5 inhibitor. BAs, also increased levels of Yes-associated protein (YAP) (associated with increased lymphangiogenesis and tumor metastasis) and several downstream mediators in the LECs. Further, TCDCA elevated several lymphangiogenic molecules such as VEGFR1, VEGFR3, FGFR2 and FGFR4, and other inflammatory chemokines and chemokine receptors that play an important role in LEC immune cell crosstalk such as CCL19, CXCL5, CCR4, CCR5. TCA on the other hand, significantly increased mRNA expression of VEGFR3, MCP1 and CCR4 indicating specific roles for the different BAs on LECs. From these data we conclude that TCDCA and TCA alters morphological and phenotypic characteristics of LECs, induces lymphangiogenesis and promotes inflammatory signaling. We also predict that these activities of BA are initiated through the FXR and TGR5 receptors and targeting these pathways could suppress lymphangiogenesis and progression of inflammation.

Cardioprotective Effect of Glycyrrhizin on Myocardial Remodeling in Diabetic Rats.

Myocardial fibrosis is one of the major complications of long-term diabetes. Hyperglycemia induced cardiomyocyte atrophy is a frequent pathophysiological indicator of diabetic heart. The objective of this study was to investigate the cardioprotective effect of glycyrrhizin (GLC) on myocardial damage in diabetic rats and assess the anti-inflammatory and anti-fibrotic effect of GLC. Our study demonstrates that hyperglycemia can elevate cardiac atrophy in diabetic animals. Type 2 diabetic fatty and the lean control rats were evaluated for cardiac damage and inflammation at 8–12 weeks after the development of diabetes. Western blot and immunohistochemical studies revealed that gap junction protein connexin-43 (CX43), cardiac injury marker troponin I, cardiac muscle specific voltage gated sodium channel NaV1.5 were significantly altered in the diabetic heart. Furthermore, oxidative stress mediator receptor for advanced glycation end-products (RAGE), as well as inflammatory mediator phospho-p38 MAPK and chemokine receptor CXCR4 were increased in the diabetic heart whereas the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), the antioxidant proteins that protect against oxidative damage was reduced. We also observed an increase in the expression of the pleiotropic cytokine, transforming growth factor beta (TGF-β) in the diabetic heart. GLC treatment exhibited a decrease in the expression of phospho-p38 MAPK, RAGE, NaV1.5 and TGF-β and it also altered the expression of CX43, CXCR4, Nrf2 and troponin I. These observations suggest that GLC possesses cardioprotective effects in diabetic cardiac atrophy and that these effects could be mediated through activation of Nrf2 and inhibition of CXCR4/SDF1 as well as TGF-β/p38MAPK signaling pathway.

Tubular epithelial cells derived-exosomes containing CD26 protects mice against renal ischemia/reperfusion injury by maintaining proliferation and dissipating inflammation

Ischemia-reperfusion injury (IR) is the leading cause of acute kidney injury (AKI). No effective drugs to treat IR-related AKI are currently available. Recent pre-clinical trials have evaluated the therapeutic potential of extracellular vesicles-exosomes to chronic kidney disease. Here, we found exosomes derived from the tubular epithelial cell in IR condition (ExoIR) enriched CD26, compared with control (ExoNormal). Tracking exosomes in vivo certified tubular epithelial cell uptake exosomes. We have isolated exosomes with overexpression of CD26 (ExoCD26+) from culture media from tubular epithelial cell line transferred by adenovirus vectors. After administration of exosomes (100 mg) or bovine serum albumin (BSA, equivalent protein control) in IR or sham operation mice after 72 h via tail vein injection, the renal function impairment and histology injury were relived in mice receiving ExoCD26+. Immunofluorescence staining with proliferating cell nuclear antigen revealed ExoCD26+ recovered proliferation of cells partly after IR injury. Cell cycle modulator, p53 and p21 were upregulated in IR mice receiving BSA control, ExoNormal, and ExoIR. ExoCD26+ significantly blunt this protein upregulation. Inflammatory cell infiltration and chemokine receptor (CXCR4) were dissipated in IR mice receiving ExoCD26+. Downstream chemokine of CXCR4, stromal derived factor-1 (SDF1) also decreased after administration of ExoCD26+ in IR mice. Finally, ExoCD26+ suppressed inundant collagenⅠ expression in IR kidney. In conclusion, Tubular epithelial cells derived-exosomes containing CD26 might be one of the therapy modes for IR-AKI by maintaining proliferation and dissipating inflammation.

The Role of Chemokines in Cardiovascular Diseases and the Therapeutic Effect of Curcumin on CXCL8 and CCL2 as Pathological Chemokines in Atherosclerosis.

Curcumin, as a vegetative flavonoid, has a protective and therapeutic role in various adverse states such as oxidative stress and inflammation. Remedial properties of this component have been reported in the different chronic diseases including cancers (myeloma, pancreatic, breast, colorectal), vitiligo, psoriasis, neuropathic pains, inflammatory disorders (osteoarthritis, uveitis, ulcerative colitis, Alzheimer), cardiovascular conditions, and diabetes.Cardiovascular disorders include atherosclerosis and various manifestations of atherosclerosis such as stroke, and myocardial infarction (MI) is the leading cause of mortality globally. Studies have shown varying expressions of inflammatory and non-inflammatory chemokines and chemokine receptors in cardiovascular disease, which have been highlighted first in this review. The alteration in chemokines secretion and chemokine receptors has an essential role in the pathophysiology of cardiovascular disease. Chemokines as cytokines with low molecular weight (8-12 kDa) mediate white blood cell (WBC) chemotactic reactions, vascular cell migration, and proliferation that induce endothelial dysfunction, atherogenesis, and cardiac hypertrophy.Several studies reported that curcumin could be advantageous in the attenuation of cardiovascular diseases via anti-inflammatory effects and redress of chemokine secretion and chemokine receptors. We present these studies with a focus on two chemokines: CXCL8 (IL-8) and CCL2 (chemoattractant protein 1 or MCP-1). Future research will further elucidate the precise potential of curcumin on chemokines in the adjustment of cardiovascular system activity or curcumin chemokine-based therapies.

The expression of repulsive guidance molecule a after traumatic brain injury: Time-course changes in gene expression in a murine model of controlled cortical impact.

Repulsive guidance molecule a (RGMa) is a key protein that negatively regulates neuronal regeneration as its inhibition enhances axonal growth and promotes functional recovery in animal models of spinal cord injury. However, the role of RGMa in traumatic brain injury (TBI) remains elusive. This study aimed to clarify TBI-responsive RGMa expression in a murine model. Adult male C57BL/6J mice were subjected to controlled cortical impact. Brains were extracted 6 hours and 1, 3, 7, 14 and 21 days after injury (n = 6 in each group). Changes in the messenger RNA (mRNA) expression of RGMa and its receptor, neogenin, were evaluated by quantitative polymerase chain reaction in the damaged area of the cortex and contralateral cortex, along with expression measurement of inflammation-related molecules. Neurological deficit was also assessed by the cylinder test. Neurological score was consistently lower in the TBI group compared to the sham group throughout the experimental period. The mRNA expressions of representative inflammatory cytokine TNF-α and chemokine receptor CCR2 were remarkably increased in the injured cortex on day 1 and gradually decreased over time, although remaining at higher values at least until day 14. The mRNA expressions of RGMa and neogenin were significantly suppressed in the damaged cortex until day 3. Interestingly, RGMa expression was suppressed most on day 1 and recovered over time. In the acute phase of TBI, gene expression of inflammatory cytokines significantly increased, and gene expressions of RGMa and neogenin significantly decreased in the inflammatory milieu of the damaged area. Despite the subsequent remission of inflammation, RGMa gene expression recovered to the normal level 1 week after TBI. Intrinsic regenerative response to acute brain injury might be hampered by the following recovery of RGMa expression, hinting at the possibility of functional RGMa inhibition as a new, effective maneuver against TBI.

Chemokine receptors (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n= 28), CXC (also known as α-chemokines; n= 17) and CX3C (n= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [684] and aliases.

CCR5 deficiency/CCR5Δ32: resistant to HIV infection at the cost of curtailed CD4+ T cell memory responses.

Orchestrated trafficking and activation by pathogen-derived peptides define the ability of CD4+ T helper cells to contribute to an effective adaptive immunity. In this issue of The EMBO Journal, Martín-Leal etal show that the inflammatory chemokine receptor CCR5, well known for its role in cell migration and HIV infection, regulates ceramide synthesis and TCR nanoclustering to promote memory CD4+ T cell activation.

Promotion of epithelial hyperplasia by interleukin-8-CXCR axis in human prostate.

The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.