CXCR1
C-X-C chemokine receptor type 1 (CXC-R1) (CXCR-1) (CDw128a) (High affinity interleukin-8 receptor A) (IL-8R A) (IL-8 receptor type 1) (CD181 antigen) [CMKAR1] [IL8RA]
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To better understand the functional state of circulating neutrophils in patients with ischemic stroke (IS) for planning future clinical trials. We analyzed by flow cytometry activation state of circulating neutrophils and the distribution of neutrophil peripheral subsets in 41 patients with acute IS less than 6 hours before admission and compared them with 22 age-matched healthy controls. Our results demonstrated continuous basal hyperactivation of circulating neutrophils during acute IS, characterized by lower l-selectin expression and higher CD11b expression at the cell surface, increased ROS production by neutrophils, and greater circulating levels of neutrophil elastase. Neutrophil hyperactivation was associated with deregulation of the equilibrium between apoptotic and necrotic. Patients also had higher percentages than controls of the overactive senescent (CXCR4 /CD62L ) neutrophil subset and increased percentage of neutrophils with a reverse transendothelial migration (CD54 CXCR1 ) phenotype. Importantly, neutrophil alterations were associated with the clinical severity of the stroke, evaluated by its NIH Stroke Scale score. Altogether, our results indicate that during acute IS, the inflammatory properties of circulating neutrophils rise, associated with the expansion of harmful neutrophil subsets. These changes in neutrophil homeostasis, associated with disease severity, may play an instrumental role by contributing to systemic inflammation and to the blood-brain barrier breakdown. Our findings highlight new potential therapeutic approaches of stroke by rebalancing the ratio of senescent to immunosuppressive neutrophils or decreasing reverse neutrophil transmigration or both.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Brain Ischemia
- CD11b Antigen
- Cell Adhesion Molecules
- Cell Death
- Cytokines
- Female
- Healthy Volunteers
- Humans
- Immunosuppression
- Inflammation
- L-Selectin
- Leukocyte Elastase
- Longitudinal Studies
- Male
- Middle Aged
- Neutrophil Activation
- Neutrophils
- Prospective Studies
- Reactive Oxygen Species
- Stroke
Mesenchymal stem cells (MSCs) have shown promise for use in cell therapy, and due to their tumor tropism can serve as vehicles for delivering therapeutic agents to tumor sites. Because interleukin-8 (IL-8) is known to mediate the protumor effect of MSCs, elimination of IL-8 secretion by MSCs may enhance their safety for use in cancer gene therapy. However, little is known concerning the effect of endogenously secreted IL-8 on MSCs. We performed studies using placenta-derived MSCs (PMSCs) to determine whether knockdown of IL-8 would influence their biological activity. We first verified that IL-8 and its membrane receptor CXCR2, but not CXCR1, were highly expressed in PMSCs. We then employed lentivirus-mediated small hairpin RNA interference to generate stable IL-8-silenced PMSCs, which displayed a variety of characteristic senescent phenotypes. We observed that at day 9 post-transfection, IL-8-silenced PMSCs had become larger and displayed a more flattened appearance when compared with their controls. Moreover, their proliferation, colony forming unit-fibroblast formation, adipogenic and osteogenic differentiation, and immunosuppressive potentials were significantly impaired. Enhanced senescence-associated β-galactosidase (SA-β-gal) activity and specific global gene expression profiles confirmed that IL-8 silencing evoked the senescence process in PMSCs. Increased levels of p-Akt and decreased levels of FOXO3a protein expression suggested that reactive oxygen species played a role in the initiation and maintenance of senescence in IL-8-silenced PMSCs. Notably, the majority of CXCR2 ligands were downregulated in presenescent IL-8-silenced PMSCs but upregulated in senescent cells, indicating an antagonistic pleiotropy of the IL-8/CXCR2 signaling pathway in PMSCs. This effect may promote the proliferation of young cells and accelerate senescence of old cells.
MeSH Terms
- Cell Proliferation
- Cellular Senescence
- Female
- Gene Knockdown Techniques
- Humans
- Interleukin-8
- Mesenchymal Stem Cells
- Placenta
- Pregnancy
- Receptors, Interleukin-8B
Keywords
- IL-8
- knockdown
- lentiviral shRNA
- mesenchymal stem cells
- placenta
- senescence
Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac-PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1. N-Ac-PGP induced DNA damage and reactive oxygen species accumulation in NP cells, which resulted in activation of the p53-p21-Rb and p16-Rb pathways. Moreover, the RT profiler PCR array showed that N-Ac-PGP down-regulates the expression of antioxidant genes in NP cells, suggesting a decline in the antioxidants of NP cells. On the other hand, N-Ac-PGP up-regulated the expression of matrix catabolic genes and inflammatory genes in NP cells. Concomitantly, N-Ac-PGP reinforced the destructive effects of senescent NP cells on the homeostasis of the IVDs in vivo. Our study suggests that N-Ac-PGP plays critical roles in the pathogenesis of IDD through the induction of premature senescence of disc cells and via the activation of catabolic and inflammatory cascades in disc cells. N-Ac-PGP also deteriorates the redox environment of disc cells. Hence, N-Ac-PGP is a new potential therapeutic target for IDD.
MeSH Terms
- Animals
- Cellular Senescence
- DNA Damage
- Glutathione
- Intervertebral Disc Degeneration
- Male
- Nucleus Pulposus
- Oligopeptides
- Rats, Sprague-Dawley
- Reactive Oxygen Species
- Receptors, Interleukin-8A
- Thioredoxins
Keywords
- Cellular antioxidant system
- Disc cell senescence
- Homeostasis of intervertebral disc
- Intervertebral disc degeneration
- Matrikine
- N-acetylated proline-glycine-proline
Dysfunctional neutrophils with advanced age are a hallmark of immunosenescence. Reduced migration and bactericidal activity increase the risk of infection. It remains unclear why neutrophil dysfunction occurs with age. Physical activity and structured exercise have been suggested to improve immune function in the elderly. The aim of this study was to assess a comprehensive range of neutrophil functions and determine their association with habitual physical activity. Physical activity levels were determined in 211 elderly (67±5years) individuals by 7-days of accelerometry wear. Twenty of the most physically active men and women were matched for age and gender to twenty of the least physically active individuals. Groups were compared for neutrophil migration, phagocytosis, oxidative burst, cell surface receptor expression, metabolic health parameters and systemic inflammation. Groups were also compared against ten young participants (23±4years). The most active group completed over twice as many steps/day as the least active group (p<0.001), had lower BMI's (p=0.007) and body fat percentages (p=0.029). Neutrophils migrated towards IL-8 better in the most active group compared to the least active (p<0.05) and was comparable to that of the young (p>0.05). These differences remained after adjusting for BMI, body fat and plasma metabolic markers which were different between groups. Correlations revealed that steps/day, higher adiponectin and lower insulin were positively associated with migratory ability (p<0.05). There was no difference in expression of the chemokine receptors CXCR1 or CXCR2 (p>0.05 for both). CD11b was higher in the most active group compared to the least active (p=0.048). No differences between activity groups or young controls were observed for neutrophil phagocytosis or oxidative burst in response to Escherichia coli (p>0.05). The young group had lower concentrations of IL-6, IL-8, MCP-1, CRP, IL-10 and IL-13 (p<0.05 for all) with no differences between the two older groups. These data suggest that impaired neutrophil migration, but not bactericidal function, in older adults may be, in part, the result of reduced physical activity. A 2-fold difference in physical activity is associated with better preserved neutrophil migratory dynamics in healthy older people. As a consequence increasing habitual physical activity may be beneficial for neutrophil mediated immunity.
MeSH Terms
- Aged
- Aging
- Cell Movement
- Exercise
- Female
- Humans
- Immunity, Innate
- Immunosenescence
- Male
- Neutrophils
Keywords
- Ageing
- Immunosenescence
- Inflammation
- Innate immunity
- Migration
- Neutrophil
- Physical activity
Neutrophils are pivotal effector cells of innate immunity representing the first line of defense against aggression. They are the first cells to arrive at the site of the aggression, where they can directly eliminate the invading microorganisms. Their activation and recruitment into peripheral tissues is indispensable for host defense. With aging, there are alterations of the receptor by driven functions of human neutrophils as a decrease in the functional changes in signaling elicited by specific receptors, as CXCR1. We investigated the activation of neutrophils from elderly after the cells were cultivated with CXCL8. Although, CXCL8 induced elastase (ELA) secretion, data showed neither myeloperoxidase (MPO) activity nor production of IL-6, IL-10, GM-CSF by neutrophils from elderly compared with young individuals. On the other hand, in the presence of only LPS or LPS associated with CXCL8 neutrophils from elderly individuals, there were significant levels of IL-6, IL-10, GM-CSF but not MPO. These results indicate that neutrophils from elderly do not respond to CXCL8 stimulus, but they are activated by LPS to produce cytokines. However, MPO activity from elderly individuals was not different in the presence or absence of LPS and CXCL8.
MeSH Terms
- Adult
- Aged
- Aging
- Humans
- Interleukin-8
- Middle Aged
- Neutrophil Activation
- Neutrophils
- Pancreatic Elastase
- Peroxidase
- Young Adult
The expression and functional activity of CXC chemokine receptors were evaluated in human osteoblasts (OB) obtained post-trauma from old donors compared to very young donors. It was found that CXCR1 and CXCR4 were only expressed by old but not young donors' cells. In contrast, CXCR3 and CXCR5 were expressed by both young and old donors. We functionally evaluated CXCR3/CXCL10 and CXCR5/CXCL13 receptor/ligand pairs by analysing cell proliferation and the release of N-acetyl-beta-D-glucosaminidase (NAG), an enzyme that degrades glycosaminoglycans and hyaluronic acid. CXCL10 and CXCL13 induced a dose-dependent increase of cell proliferation in OB from young donors while cell proliferation of OB in old donors was not affected. By contrast, CXCL10 and CXCL13 induced a significantly higher NAG release in OB from old donors compared to young ones. These data demonstrate a significant age-dependent difference in the response of OB to CXCL10 and CXCL13 stimulation. These chemokines induce an inverse response of OB from old and young donors, which suggests a role of ageing in the modulation of cellular response of bone cells.
MeSH Terms
- Aged
- Aging
- Alkaline Phosphatase
- Cell Division
- Cells, Cultured
- Chemokine CXCL10
- Chemokine CXCL13
- Chemokines, CXC
- Child, Preschool
- Humans
- Infant
- Osteoblasts
- Receptors, CXCR3
- Receptors, CXCR5
- Receptors, Chemokine
- Receptors, Cytokine
Increasing evidence suggests that the chemokine interleukin (IL)-8/CXCL8 plays important roles in CNS development, neuronal survival, modulation of excitability, and neuroimmune response. Recently, we have shown that CXCL8 can acutely modulate ion channel activity in septal neurons expressing receptors CXCR1 and/or CXCR2. This was a surprising finding, insofar as CXCR1 expression had not been described for the mammalian brain. Here we investigated whether CXCR1 transcripts are present in other brain regions, whether they are expressed at the single-cell level in molecularly identified neurons and astrocytes, and how they are regulated during early postnatal development. In addition, possible cellular colocalization of CXCR1 and CXCR2 transcripts was examined. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) revealed that CXCR1 mRNAs were expressed in the septum, striatum, hippocampus, cerebellum, and cortex (temporoparietal and entorhinal) at different levels and appeared to be regulated independently from CXCR2 during development. By using RT multiplex PCR on acutely dissociated cells from these brain regions, we show that CXCR1 transcripts were expressed in 83% of 84 sampled neurons displaying cholinergic (choline acetyltransferase mRNAs), gamma-aminobutyric acidergic (glutamic acid decarboxylases 65 and 67 mRNAs), or glutamatergic (vesicular glutamate transporters 1 and 2 mRNAs) phenotypes. CXCR1 and CXCR2 transcripts were colocalized in 45% of neurons sampled and also were present in some glial fibrillary acidic protein mRNA-expressing astrocytes. This is the first study to demonstrate the widespread expression of CXCR1 transcripts in the brain and suggests that CXCR1 may have hitherto unsuspected roles in neuromodulation and inflammation.
MeSH Terms
- Acetylcholine
- Aging
- Animals
- Animals, Newborn
- Astrocytes
- Brain
- Cell Line
- Cell Separation
- Female
- Glutamic Acid
- Neurons
- RNA, Messenger
- Rats
- Rats, Sprague-Dawley
- Receptors, Interleukin-8A
- Receptors, Interleukin-8B
- gamma-Aminobutyric Acid