CCR1
C-C chemokine receptor type 1 (C-C CKR-1) (CC-CKR-1) (CCR-1) (CCR1) (HM145) (LD78 receptor) (Macrophage inflammatory protein 1-alpha receptor) (MIP-1alpha-R) (RANTES-R) (CD191 antigen) [CMKBR1] [CMKR1] [SCYAR1]
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In this study, we examined the combined effect of aging and myocardial infarction on left ventricular remodeling, focusing on matrix metalloproteinase (MMP)-9-dependent mechanisms. We enrolled 55 C57BL/6J wild type (WT) and 85 MMP-9 Null (Null) mice of both sexes at 11-36 months of age and evaluated their response at Day 7 post-myocardial infarction. Plasma MMP-9 levels positively linked to age in WT mice (r = .46, p = .001). MMP-9 deletion improved survival (76% for WT vs 88% for Null, p = .021). Post-myocardial infarction, there was a progressive increase in left ventricular dilation with age in WT but not in Null mice. By inflammatory gene array analysis, WT mice showed linear age-dependent increases in three different proinflammatory genes (C3, CCl4, and CX3CL1; all p < .05), whereas Null mice showed increases in three proinflammatory genes (CCL5, CCL9, and CXCL4; all p < .05) and seven anti-inflammatory genes (CCL1, CCL6, CCR1, IL11, IL1r2, IL8rb, and Mif; all p < .05). Compared with WT, macrophages isolated from Null left ventricle infarct demonstrated enhanced expression of anti-inflammatory M2 markers CD163, MRC1, TGF-β1, and YM1 (all p < .05), without affecting proinflammatory M1 markers. In conclusion, MMP-9 deletion stimulated anti-inflammatory polarization of macrophages to attenuate left ventricle dysfunction in the aging post-myocardial infarction.
MeSH Terms
- Aging
- Animals
- Cytokines
- Echocardiography
- Female
- Gene Expression
- Immunohistochemistry
- Ligation
- Male
- Matrix Metalloproteinase 9
- Mice
- Mice, Inbred C57BL
- Myocardial Infarction
- Real-Time Polymerase Chain Reaction
- Survival Analysis
- Ventricular Remodeling
Keywords
- Aging
- Cardiac remodeling
- M2 phenotype.
- Macrophage polarization
Chemokine receptors are reported to be involved in neuronal cell death and CNS neurodegenerative diseases. The aim of the current study was to investigate the expression of CCR1, a major chemokine receptor for CC chemokines in retinal dystrophy in rd (retinal degeneration) mice and further explore its role in photoreceptor degeneration. The expression levels of CCR1 mRNA in the whole control and rd retinas at postnatal days (P) 8, 10, 12, 14, 16, and 18 were determined by RT-PCR assay. Location of CCR1 in the retina of rd mice at each age group was studied by immunohistochemical analysis. Expression of CCR1 in the photoreceptor cells and apoptotic cells was determined by double labeling. Expression of CCR1 mRNA was noted in both control and rd retinas at each age group. CCR1-positive cells started to emerge in the outer nuclear layer (ONL) in rd retinas at P8 and reached a peak at P12 and P14. Double labeling of CCR1 with rhodopsin, CD11b, or TUNEL staining showed expression of CCR1 in the photoreceptor cells, rather than in the microglial cells. Partial CCR1 expression was observed in some of the apoptotic photoreceptor cells. Expression of CCR1 in the photoreceptor cells was increased with the progress of retinal degeneration in rd mice. Activation of CCR1 may play a role in the photoreceptor apoptosis.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Apoptosis
- CD11b Antigen
- Fluorescent Antibody Technique, Indirect
- Gene Expression Regulation
- In Situ Nick-End Labeling
- Mice
- Mice, Inbred C3H
- Mice, Mutant Strains
- Photoreceptor Cells, Vertebrate
- RNA, Messenger
- Receptors, CCR1
- Retinal Degeneration
- Reverse Transcriptase Polymerase Chain Reaction
- Rhodopsin
Leukocyte chemokine receptors (CR) are central to the pathogenesis of many human diseases, including human immunodeficiency virus-1 (HIV-1) infection. Elderly individuals infected with the HIV-1 virus have a shorter disease-free interval and worse clinic outcome. However, the reasons for this are unclear. We recently reported increased CC chemokine receptor (CCR) expression in CD4 T cells in aged mice, but it is not known if similar changes occur in humans. In addition, it is unclear if the observed differences are related to aged-related expansion in the memory T cell compartment. In this report, we examined the effects of aging on CCR gene expression in human peripheral blood mononuclear cells (PBMCs), CD4 T cells, and naive/memory T cells. Aging is found to be associated with increased CCR1-5 expression in PBMCs and CD4 T cells. In addition, although the age-related increases in CCR expression occurred in both naive and memory T cells, the greatest changes were seen in the memory T cell subset. We propose that the observed aging-associated increase in T cell chemokine receptor expression may contribute to the worse clinical outcome of T cell chemokine receptor-dependent disease, such as HIV-1 infection, in the elderly.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Chemokines, CC
- Humans
- Immunologic Memory
- Middle Aged
- Receptors, Chemokine
Changes in chemokine receptor expression are important in determining T cell migration and the subsequent immune response. To better understand the contribution of the chemokine system in immune senescence we determined the effect of aging on CD4( ) T cell chemokine receptor function using microarray, RNase protection assays, Western blot, and in vitro chemokine transmigration assays. Freshly isolated CD4( ) cells from aged (20-22 mo) mice were found to express a higher level of CCR1, 2, 4, 5, 6, and 8 and CXCR2-5, and a lower level of CCR7 and 9 than those from young (3-4 mo) animals. Caloric restriction partially or completely restored the aging effects on CCR1, 7, and 8 and CXCR2, 4, and 5. The aging-associated differences in chemokine receptor expression cannot be adequately explained by the age-associated shift in the naive/memory or Th1/Th2 profile. CD4( ) cells from aged animals have increased chemotactic response to stromal cell-derived factor-1 and macrophage-inflammatory protein-1alpha, suggesting that the observed chemokine receptor changes have important functional consequences. We propose that the aging-associated changes in T cell chemokine receptor expression may contribute to the different clinical outcome in T cell chemokine receptor-dependent diseases in the elderly.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Caloric Restriction
- Cells, Cultured
- Chemotaxis, Leukocyte
- Mice
- Mice, Inbred C57BL
- Mice, Inbred DBA
- RNA Probes
- RNA Stability
- RNA, Messenger
- Receptors, Chemokine
- Ribonucleases
- T-Lymphocyte Subsets
- Th1 Cells
- Th2 Cells
While numerous previous studies have investigated age-related changes of cytokine production, little is known about chemokines, the importance of which in regulating immune response is becoming increasingly evident. In this study, a group of healthy subjects over 90 years old is compared to a group of young subjects, we evaluated the ability of monocytes, T lymphocytes and NK cells: (1) to produce RANTES and MIP-1alpha, either in basal conditions or after stimulation with, respectively, LPS, anti-CD3 MoAb and IL-2; (2) to express the corresponding chemokine receptors (CCR1, CCR3, CCR5). We demonstrate that: (a) monocytes, T lymphocytes and NK cells spontaneously produced detectable amounts of chemokines, both in young and old subjects; (b) monocyte-dependent RANTES and MIP-1alpha production induced by LPS was up-regulated in nonagenarian subjects as anti-CD3-induced secretion from T cells; (c) RANTES and MIP-1alpha production by IL-2 stimulated NK cells was reduced in elderly subjects; (d) CCR1, CCR3 and CCR5 were widely expressed on monocytes, but less expressed on T lymphocytes and NK cells. The diversity within PBMC might reflect their different states of activation and/or responsiveness, influencing the ability to develop rapid innate and long-lasting adaptive immune responses.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cells, Cultured
- Chemokine CCL3
- Chemokine CCL4
- Chemokine CCL5
- Female
- Humans
- Killer Cells, Natural
- Lipopolysaccharides
- Macrophage Inflammatory Proteins
- Male
- Monocytes
- Receptors, CCR1
- Receptors, CCR3
- Receptors, CCR5
- Receptors, Chemokine
- T-Lymphocytes