CXCR3
C-X-C chemokine receptor type 3 (CXC-R3) (CXCR-3) (CKR-L2) (G protein-coupled receptor 9) (Interferon-inducible protein 10 receptor) (IP-10 receptor) (CD183 antigen) [GPR9]
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Impaired muscle regeneration and increased muscle fibrosis are observed in aged muscle accompanied by progressive loss of muscle mass (sarcopenia). However, the underlying mechanism is still unclear. The differentiated expressed genes in young and aged muscles after acute injury by cardiotoxin were identified by RNA-sequence analysis. Single-cell RNA-sequence analysis was used to identify cell clusters and functions in young muscle after acute injury, and flow cytometry analysis and sorting were used to validate the function. The proliferation and differentiation functions of satellite cells were accessed by immunostaining with 5-ethynyl-2'-deoxyuridine and embryonic myosin heavy chain (eMyHC), respectively. Muscle regeneration ability was accessed by histopathological and molecular biological methods. Gene expression patterns associated with responses to interferon-gamma (IFN-γ) (15 genes; false discovery rate < 0.001) were significantly down-regulated during muscle regeneration in aged mice (P = 2.25e-7). CD8 T cells were the main source of increased IFN-γ after injury, adoptive transfer of wild-type CD8 T cells to IFN-γ-deficient young mice resulted in 78% increase in cross-sectional areas (CSAs) of regenerated myofibres (P < 0.05) and 63% decrease in muscle fibrosis (P < 0.05) after injury. Single-cell RNA-sequence analysis identified a novel subset of macrophages [named as IFN-responsive macrophages (IFNRMs)] that specifically expressed IFN-responsive genes (Ifit3, Isg15, Irf7, etc.) in young mice at 3 days after injury, and the number of this macrophage subset was ~20% lower in aged mice at the same time (P < 0.05). IFNRMs secreted cytokine C-X-C motif chemokine 10 (CXCL10) that promoted the proliferation and differentiation of satellite cells via its receptor, CXCR3. Intramuscular recombinant CXCL10 treatment in aged mice rejuvenated the proliferation of satellite cells (80% increase in Ki-67 Pax7 cells, P < 0.01) and resulted in 27% increase in CSA of regenerated myofibres (P < 0.01) and 29% decrease in muscle fibrosis (P < 0.05). Our study indicates that decline in IFN-γ response in a novel subset of macrophage contributes to satellite cells dysfunctions in aged skeletal muscles and demonstrates that this mechanism can be targeted to restore age-associated myogenesis.
Keywords
- Aging
- CXCL10
- IFN-γ
- Macrophage
- Muscle regeneration
- Single-cell RNA sequence
The effects of senescence associated secretory phenotype (SASP) from therapy-induced senescent endothelial cells on tumor microenvironment (TME) remains to be clarified. Here, we investigated effects of ionizing radiation (IR)- and doxorubicin-induced senescent HUVEC on TME. MDA-MB-231 cancer cells treated with conditioned medium (CM) from senescent HUVEC or co-cultured with senescent HUVEC significantly increased cancer cell proliferation, migration, and invasion. We found that CXCL11 plays a principal role in the senescent CM-induced aggressive activities of MDA-MB-231 cells. When we treated HUVEC with a neutralizing anti-CXCL11 antibody or CXCL11 SiRNA, or treated MDA-MB-231 cells with CXCR3 SiRNA, we observed synergistic diminution of the ability of the HUVEC SASP to alter the migration and spheroid invasion of cancer cells. ERK activation was involved in the HUVEC SASP-induced aggressive activity of MDA-MB-231 cells. Finally, we observed the in vivo effect of CXCL11 from the senescent HUVEC in tumor-bearing mice. Together, our results demonstrate that SASP from endothelial cells experiencing therapy-induced senescence promotes the aggressive behavior of cancer cells, and that CXCL11 can potentially be targeted to prevent the adverse effects of therapy-induced senescent endothelial cells on the tumor microenvironment.
Keywords
- CXCL11
- Endothelial cells
- Therapy-induced senescence
- Tumor microenvironment
Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16 during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Atrophy
- Cells, Cultured
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Epidermis
- Female
- Humans
- Male
- Melanocytes
- Middle Aged
- Paracrine Communication
- Reactive Oxygen Species
- Receptors, CXCR4
- Skin
- Telomere
- Young Adult
Keywords
SASP
- melanocytes
- senescence
- skin ageing
- telomeres
Cellular senescence and natural killer (NK) cells play an important role in liver diseases. Chemokines, a component of the senescence-associated secretory phenotype, can recruit NK cells and are involved in the development of various liver diseases. The effect of the C-X-C motif chemokine ligand (CXCL)-9, -10, -11/C-X-C motif chemokine receptor (CXCR)3 axis in senescent hepatocytes remains unknown. The chemokines secreted by senescent hepatocytes, the contribution of the CXCL-9, -10, -11/CXCR3 axis to the migration of NK cells, and the effect of senescent hepatocytes on the function of NK cells were investigated in the present study. The results demonstrated significantly increased levels of C-C motif chemokine ligand 2 and CXCL-1, -2 and -10 in the supernatant of senescent AML12 cells. Despite increased mRNA expression of CXCL-9, -10, and -11 in these cells, western blotting revealed significantly enhanced expression of only CXCL-10. The expression of CXCR3 on the surface of NK cells stimulated by senescent AML12 cells was upregulated (fold change, >3). Following incubation with the supernatant of senescent hepatocytes, both CD107a and interferon γ expression in NK cells increased by >2.5-fold. The cytotoxic effect of NK cells was notably higher stimulated by senescent AML12 cells. Chemotaxis and blocking assays demonstrated that the senescent hepatocytes enhanced the migration of NK cells via the CXCL-10/CXCR3 axis. The present study suggests that senescent hepatocytes secrete various chemokines, including CXCL-10, resulting in the upregulation and activation of CXCR3 in NK cells and the enhancement of NK cell migration via the CXCL-10/CXCR3 axis.
Keywords
- chemokine
- hepatocyte
- natural killer cell
- senescence
Aging is a significant risk factor for dry eye. Here we used a murine aging model to investigate the effects of aging on antigen presenting cells (APCs) and generation of pathogenic T helper (Th)-1 cells. Our results showed that APCs from aged mice accumulate at the conjunctiva, have higher levels of co-activation marker CD86 and lower aldehyde dehydrogenase activity. Using topical ovalbumin peptide as a surrogate antigen, we observed an increased number of antigen-loaded APCs in the draining cervical lymph nodes in the aged group and loss of tight junction protein occludin in the conjunctiva. Aged cervical lymph nodes APCs showed a greater generation of Th1 cells than young APCs in antigen-presentation assays in vitro. Aged lacrimal glands, and draining nodes showed an accumulation of IFN-γ producing CD4 T cells, while Th-17 cells were present only in aged draining nodes. There was also an age-related increase in CD4 CXCR3 IFN-γ cells in the conjunctiva, nodes, and lacrimal glands while CD4 CCR6 IL-17A cells increased in the draining nodes of aged mice. Adoptive transfer of aged CD4 CXCR3 cells into young, naive immunodeficient recipients caused greater goblet cell loss than young CD4 CXCR3 donor cells. Our results demonstrate that age-associated changes in APCs are critical for the pathogenesis of age-related dry eye.
MeSH Terms
- Adoptive Transfer
- Aging
- Animals
- Antigen-Presenting Cells
- Biomarkers
- Cellular Senescence
- Cytokines
- Disease Models, Animal
- Dry Eye Syndromes
- Female
- Lymphocyte Activation
- Mice
- Mice, Knockout
- Th1 Cells
Naïve phenotype (NP) T cells spontaneously initiate homeostatic proliferation (HP) as T-cell output is reduced because of physiologic thymic involution with age. However, the effects of sustained HP on overall immune function are poorly understood. We demonstrated that the NP CD8 T cell population in adult thymectomized mice showing accelerated HP has an increased capacity for TCR-mediated interferon-γ and tumor necrosis factor α production, which is attributed to an increase in CXCR3 cells in the NP CD8 T cell population. The CXCR3 NP CD8 T cells developed during persistent HP with a slow cell division rate, but rarely during robust antigen-driven proliferation with a fast cell division rate. In ontogeny, the proportions of CXCR3 cells in the NP CD8 T cell population showed a biphasic profile, which was high at the newborn and aged stages. Upon transfer, CXCR3 NP CD8 T cells, but not CXCR3 NP CD8 T cells, potently enhanced Th17-mediated inflammatory tissue reactions in vivo. Furthermore, CXCR3 NP CD8 T cells with similar features were also detected at variable levels in healthy human blood. These results suggest that CXCR3 NP CD8 T cells generated during physiological HP significantly impact overall immunity at the immunologically vulnerable neonatal and aged stages.
MeSH Terms
- Aging
- Animals
- CD8-Positive T-Lymphocytes
- Cell Division
- Cell Proliferation
- Cells, Cultured
- Flow Cytometry
- Homeostasis
- Humans
- Interferon-gamma
- Lymphocyte Activation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phenotype
- Receptors, CXCR3
- Th17 Cells
Keywords
- CD8 T cells
- CXCR3
- Homeostatic proliferation
- Thymic involution
- T cell aging
Vaccination remains the most cost-effective biomedical approach for controlling influenza disease. In times of pandemics, however, these vaccines cannot be produced in sufficient quantities for worldwide use by the current manufacturing capacities and practices. What is needed is the development of adjuvanted vaccines capable of inducing an adequate or better immune response at a decreased antigen dose. Previously we showed that the protein adjuvant rOv-ASP-1 augments influenza-specific antibody titers and survival after virus challenge in both young adult and old-age mice when administered with the trivalent inactivated influenza vaccine (IIV3). In this study we show that a reduced amount of rOv-ASP-1, with 40-times less IIV3 can also induce protection. Apparently the potency of the rOv-ASP-1 adjuvanted IIV3 vaccine is independent of the IIV3-specific Th1/Th2 associated antibody responses, and independent of the presence of HAI antibodies. However, CD4 T helper cells were indispensable for the protection. Further, rOv-ASP-1 with or without IIV3 elicited the increased level of various chemokines, which are known chemoattractant for immune cells, into the muscle 4 h after immunization, and significantly induced the recruitment of monocytes, macrophages and neutrophils into the muscles. The recruited monocytes had higher expression of the activation marker MHCII on their surface as well as CXCR3 and CCR2; receptors for IP-10 and MCP-1, respectively. These results show that the rOv-ASP-1 adjuvant allows substantial antigen sparing of IIV3 by stimulating at the site of injection the accumulation of chemokines and the recruitment of immune cells that can augment the activation of CD4 T cell immune responses, essential for the production of antibody responses. Protection elicited by the rOv-ASP-1 adjuvanted IIV3 vaccine also appears to function in the absence of MyD88-signaling. Future studies will attempt to delineate the precise mechanisms by which the rOv-ASP-1 adjuvanted IIV3 vaccine works.
MeSH Terms
- Adjuvants, Immunologic
- Aging
- Animals
- Antibodies, Viral
- Antigens, Helminth
- Female
- Gene Expression Regulation
- Helminth Proteins
- Histocompatibility Antigens Class II
- Immunization
- Influenza Vaccines
- Macrophages
- Mice
- Mice, Knockout
- Monocytes
- Muscle, Skeletal
- Myeloid Differentiation Factor 88
- Neutrophils
- Orthomyxoviridae Infections
- Receptors, CCR2
- Receptors, CXCR3
- Survival Analysis
- T-Lymphocytes, Helper-Inducer
- Viral Load
Keywords
- Adjuvant
- Antibody isotypes
- Antigen-sparing
- Cell recruitment
- Chemokines
- Immune response
Immune senescence is a natural consequence of aging and may contribute to frailty and loss of homeostasis in later life. Calorie restriction increases healthy life-span in C57BL/6J (but not DBA/2J) mice, but whether this is related to preservation of immune function, and how it interacts with aging, is unclear. We compared phenotypic and functional characteristics of natural killer (NK) cells and T cells, across the lifespan, of calorie-restricted (CR) and control C57BL/6 and DBA/2 mice. Calorie restriction preserves a naïve T cell phenotype and an immature NK cell phenotype as mice age. The splenic T cell populations of CR mice had higher proportions of CD11a CD44 cells, lower expression of TRAIL, KLRG1, and CXCR3, and higher expression of CD127, compared to control mice. Similarly, splenic NK cells from CR mice had higher proportions of less differentiated CD11b CD27 cells and correspondingly lower proportions of highly differentiated CD11b CD27 NK cells. Within each of these subsets, cells from CR mice had higher expression of CD127, CD25, TRAIL, NKG2A/C/E, and CXCR3 and lower expression of KLRG1 and Ly49 receptors compared to controls. The effects of calorie restriction on lymphoid cell populations in lung, liver, and lymph nodes were identical to those seen in the spleen, indicating that this is a system-wide effect. The impact of calorie restriction on NK cell and T cell maturation is much more profound than the effect of aging and, indeed, calorie restriction attenuates these age-associated changes. Importantly, the effects of calorie restriction on lymphocyte maturation were more marked in C57BL/6 than in DBA/2J mice indicating that delayed lymphocyte maturation correlates with extended lifespan. These findings have implications for understanding the interaction between nutritional status, immunity, and healthy lifespan in aging populations.
Keywords
- T cell
- aging
- calorie restriction
- differentiation
- maturation
- natural killer cell
The pathogenic role and frequency of T cell subtypes in early rheumatoid arthritis are still unclear. We therefore performed a comprehensive analysis of the circulating T cell subtype pattern in patients with untreated early rheumatoid arthritis compared to healthy control subjects. Peripheral blood mononuclear cells were obtained from 26 patients with untreated early rheumatoid arthritis and from with 18 age- and sex-matched healthy control subjects. T helper cell types Th0, Th1, Th2, Th17, and Th1/17 and nonclassic T helper subsets were defined by flow cytometry based on the expression of chemokine receptors CCR4, CCR6, and CXCR3. Regulatory T cells were defined by expression of CD25 CD127 and also FOXP3 CXCR5 cells among regulatory and nonregulatory T cells were defined as T follicular regulatory and T follicular helper cells, respectively. The phenotype of T cell subsets was confirmed by transcription factor and cytokine secretion analyses. Multivariate discriminant analysis showed that patients with untreated early rheumatoid arthritis were segregated from healthy control subjects based on the circulating T cell subset profile. Among the discriminator subsets, CCR4 CXCR3 (Th2 and Th17), CTLA4 and FOXP3 subsets were present in significantly higher frequencies, whereas CCR4 (Th1/Th17, CCR6 CCR4 CXCR3 , and Th1) subsets were present in lower frequencies in patients with untreated early rheumatoid arthritis compared with healthy control subjects. The proportions of Th2 and Th17 subsets associated positively with each other and negatively with the CXCR3 /interferon γ-secreting subsets (Th1 and Th1/Th17) in patients with untreated rheumatoid arthritis. The proportions of Th2 cells increased with age in patients with untreated early rheumatoid arthritis and healthy control subjects. The dominance of circulating CCR4 CXCR3 T helper subsets (Th2 and Th17) in untreated early rheumatoid arthritis point toward a pathogenic role of these cells in early stages of the disease.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, Differentiation, T-Lymphocyte
- Arthritis, Rheumatoid
- Case-Control Studies
- Cytokines
- Disease Progression
- Female
- Flow Cytometry
- Gene Expression Profiling
- Humans
- Immunophenotyping
- Lymphocyte Count
- Male
- Middle Aged
- Receptors, CXCR3
- T-Lymphocyte Subsets
- T-Lymphocytes, Helper-Inducer
- T-Lymphocytes, Regulatory
- Transcription Factors
Keywords
- T cell profile
- autoimmunity
- chemokine receptors
- multivariate discriminant analysis
The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG( )IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete granzyme B (GrB), which plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance. Our data demonstrate that in the elderly, naïve/memory B cell populations present a different expression of the studied receptors that could be discussed in terms of "inflamm-aging". In particular IgG( )IgD(-)CD27(-) DN B cells show a tissue trafficking phenotype and they can be stimulated to produce GrB.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocyte Subsets
- Granzymes
- Humans
- Immunoglobulin D
- Immunoglobulin G
- Interleukins
- L-Selectin
- Phenotype
- Receptors, CXCR
- Tumor Necrosis Factor Receptor Superfamily, Member 7
Keywords
- B lymphocytes
- Chemokine receptors
- Elderly
- Granzyme B
- IL-21
- Inflamm-aging
The number of memory phenotype CD8 T cells increases dramatically with aging in both humans and mice. However, the mechanism for this is unknown. The prevailing hypothesis is that memory T cells accumulate with aging as a result of lifelong antigenic stimulation. However, data supporting this supposition are lacking. In this study, we demonstrate that central memory CD8 T cells, which represent a large majority of memory CD8 T cells in aged mice, are not memory cells that develop in response to antigenic stimulation but are virtual memory cells that develop without antigenic stimulation. In addition to phenotypic evidence, we show that accumulation of central memory CD8 T cells is independent of CD4 T cells, CCR5, and CXCR3, all of which are known to be essential for Ag-driven development of central memory CD8 T cells. Thus, this study reveals a novel mechanism for aging-related changes in CD8 T cells.
MeSH Terms
- Aging
- Animals
- Antigens
- CD4 Antigens
- CD8-Positive T-Lymphocytes
- Female
- Hyaluronan Receptors
- Immunologic Memory
- Interleukin-15
- L-Selectin
- Lymphocyte Count
- Lymphopoiesis
- Male
- Mice
- Mice, Congenic
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Immunological
- Radiation Chimera
- Receptors, CCR5
- Receptors, CXCR3
- T-Lymphocyte Subsets
{{medline-entry |title=Altered Th1/Th2 commitment contributes to lung senescence in CXCR3-deficient mice. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23583952 |abstract=Aging is an inevitable process associated with immune imbalance, which is characterized by a progressive functional decline in major organs, including lung. However, effects of altered Th1/Th2 commitment on lung senescence are largely unknown. To examine effects of altered Th1/Th2 balance on lung aging, we measured proportions of Th1 and Th2 cells and expression of cytokines, chemokines, collagen deposition and other relevant physiological and pathological parameters in 2- and 20-months-old (mo) CXCR3-deficient (CXCR3(-/-)) C57BL/6J mice compared with wild-type (WT) mice. There was a significant weight-loss observed in 20-mo CXCR3(-/-) mice compared with the same aged WT group. Although lung function and structure changed with age in both groups, central airway resistance (Rn), tissue elastance (H) and damping (G) were significantly lower in 20-mo CXCR3(-/-) mice than those of WT mice. In contrast, the whole lung volume (V(L)), the mean linear intercept length of alveolar (L(m)), and the total lung collagen content were significantly elevated in 20-mo CXCR3(-/-) mice. With aging, the lungs of WT mice had typical Th1-type status (increased population of Th1 cells and concentrations of cytokine IFN-γ and CXCR3 ligands) while CXCR3(-/-) mice showed Th2-type polarization (decreased proportion of Th1 cells and concentrations of CXCR3 ligands but increased level of IL-4). Our data suggest that Immunosenescence is associated with lung aging, and that altered Th1/Th2 imbalance favors Th2 predominance in CXCR3(-/-) mice, which contributes to the process of accelerated lung aging in this model. |mesh-terms=* Aging
- Animals
- Cell Count
- Chemokines
- Collagen
- Cytokines
- Lung
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- Organ Size
- Receptors, CXCR3
- Th1 Cells
- Th1-Th2 Balance
- Th2 Cells
|keywords=* B6
- BALF
- C57BL/6J inbred mouse strain
- CCR
- CXCL
- CXCR
- CXCR3
- C–C chemokine receptor
- D2
- DBA/2J inbred mouse strain
- ELISA
- Enzyme-linked immunosorbent assay
- FEV(1)
- FRC
- FVC
- G
- H
- H