CCL21
C-C motif chemokine 21 precursor (6Ckine) (Beta-chemokine exodus-2) (Secondary lymphoid-tissue chemokine) (SLC) (Small-inducible cytokine A21) [SCYA21] [UNQ784/PRO1600]
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Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the chemokine receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.
MeSH Terms
- Aging
- Animals
- Bone and Bones
- Cartilage
- Cell Differentiation
- Cell Movement
- Cells, Cultured
- Chemokine CCL21
- Chondrocytes
- Chondrogenesis
- Female
- Mesenchymal Stem Cells
- Mice, Inbred C57BL
- Rabbits
- Receptors, CCR7
- Signal Transduction
- Wound Healing
[i]Klotho (KL)[/i] encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the [i]KL[/i] gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of target genes. KL participates in modulation of the insulin/insulin-like growth factor-1 (IGF-1) signaling, which induces the growth hormone (GH) secretion. Accordingly, [i]KL[/i] mutant mice display multiple aging-like phenotypes, which are ameliorated by overexpression of KL. Therefore, KL is an important contributor to lifespan. KL is further identified as a regulator of calcium (Ca ) channel-dependent cell physiological processes. KL has been also shown to induce cancer cell apoptosis, thus, it is considered as a potential tumor suppressor. Our recent studies have indicated that KL modulates an influx of Ca from the extracellular space, leading to a change in CCL21-dependent migration in dendritic cells (DCs). Interestingly, the regulation of the expression of KL was mediated through a phosphoinositide 3-kinase (PI3K) pathway in DCs. Moreover, downregulating of KL expression by using siRNA knockdown technique, we observed that the expression of Ca channels including Orai3, but not Orai1, Orai2, TRPV5 and TRPV6 was significantly reduced in [i]KL[/i]-silenced as compared to control BMDCs. Clearly, additional research is required to define the role of KL in the regulation of organismic and cellular functions through the PI3K signaling and the expression of the Ca channels.
Keywords
- Aging
- Calcium channel
- Cancer
- Dendritic cells
- Klotho
Artery tertiary lymphoid organs (ATLOs) are atherosclerosis-associated lymphoid aggregates with varying degrees of complexity ranging from small T/B-cell clusters to well-structured lymph node-like though unencapsulated lymphoid tissues. ATLOs arise in the connective tissue that surrounds diseased arteries, i.e., the adventitia. ATLOs have been identified in aged atherosclerosis-prone hyperlipidemic apolipoprotein E-deficient (ApoE ) mice: they are organized into distinct immune cell compartments, including separate T-cell areas, activated B-cell follicles, and plasma cell niches. Analyses of ATLO immune cell subsets indicate antigen-specific T- and B-cell immune reactions within the atherosclerotic arterial wall adventitia. Moreover, ATLOs harbor innate immune cells, including a large component of inflammatory macrophages, B-1 cells, and an aberrant set of antigen-presenting cells. There is marked neoangiogenesis, irregular lymphangiogenesis, neoformation of high endothelial venules, and [i]de novo[/i] synthesis of lymph node-like conduits. Molecular mechanisms of ATLO formation remain to be identified though media vascular smooth muscle cells may adopt features of lymphoid tissue organizer-like cells by expressing lymphorganogenic chemokines, i.e., CXCL13 and CCL21. Although these data are consistent with the view that ATLOs participate in primary T- and B-cell responses against elusive atherosclerosis-specific autoantigens, their specific protective or disease-promoting roles remain to be identified. In this review, we discuss what is currently known about ATLOs and their potential impact on atherosclerosis and make attempts to define challenges ahead.
Keywords
- adventitia
- aging
- artery tertiary lymphoid organs
- atherosclerosis
- autoimmune responses
In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c( ) B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c( ) B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity.
MeSH Terms
- Aging
- Animals
- Antigen-Presenting Cells
- Autoantibodies
- Autoimmunity
- B-Lymphocytes
- CD11c Antigen
- Chemokine CCL19
- Chemokine CCL21
- Female
- Gene Expression Regulation
- Mice
- Mice, Inbred C57BL
- Receptors, CCR7
- Signal Transduction
- Spleen
- T-Lymphocytes
Lenalidomide, an analog of thalidomide, modified responses of stimulated T cells from healthy young (ages 21-40 years) and old (≥ age 65 years) subjects. At 0.03 μM to 1 μM, lenalidomide enhanced generation of IL-2 and IFN-γ by T cell receptor-stimulated T cells of young subjects up to respective maximum increases of 17-fold and three-fold, but at 0.3 μM and 1 μM suppressed IL-17 generation. The same concentrations of lenalidomide enhanced IL-2 and IFN-γ generation by stimulated T cells of old subjects more, with greater respective maximal increases of up to 120-fold and six-fold, without suppressing IL-17 generation. Lenalidomide enhanced proliferation and suppressed apoptosis of stimulated T cells from old subjects, by IL-2-dependent mechanisms, and restored diminished T cell chemotactic responses to CCL21 and sphingosine 1-phosphate. The reversal of T cell abnormalities of immunosenescence by low concentrations of lenalidomide suggest a potential for improvement of immunity in the elderly.
MeSH Terms
- Adult
- Aged
- Aging
- Cell Proliferation
- Cell Survival
- Cells, Cultured
- Chemokine CCL21
- Chemotaxis
- Cytokines
- Female
- Humans
- Lenalidomide
- Lymphocyte Activation
- Male
- Monocytes
- T-Lymphocytes
- Thalidomide
- Young Adult
- bcl-X Protein
Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE(-/-) mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin beta receptor (LTbetaR) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE(-/-) mice with LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.
MeSH Terms
- Aging
- Animals
- Aorta, Abdominal
- Apolipoproteins E
- Atherosclerosis
- Biological Transport
- Cells, Cultured
- Chemokine CCL21
- Chemokine CXCL13
- Cluster Analysis
- Connective Tissue
- Gene Expression Profiling
- In Situ Hybridization
- Leukocytes, Mononuclear
- Lymphoid Tissue
- Lymphotoxin beta Receptor
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myocytes, Smooth Muscle
- Organogenesis
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Tunica Intima
- Tunica Media
We recently reported that bone marrow-derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide((257-264)), DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3-grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide((257-264))-pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific CD8( ) T cells in vivo. Effector functions of these T cells, as determined by IFN-gamma production and cytotoxic activity, were similar to those obtained from mice vaccinated with young OVA PP-DCs. A decreased influx of intratumor CD8( ) T cells was also observed. Importantly, although defective in vivo migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8( ) T-cell induction remained. Taken together, our findings suggest that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Cell Proliferation
- Dendritic Cells
- Electrophoresis, Polyacrylamide Gel
- Mice
- Mice, Inbred C57BL
- Ovalbumin
To explore the biological significance of the lymphatics in the autoimmune process, the thymus from non-obese diabetic (NOD) mice was evaluated by histochemistry and western blot analysis. Thymic lymphatic endothelial cells showed suggestive expression patterns of the functional molecules lymphatic vascular endothelial hyaluronan receptor (LYVE)-1, CCL21, CD31 and podoplanin. With increasing age, the expression of CCL21 was reduced in the medullary epithelial cells and lymphatics. Of note, LYVE-1-expressing lymphatics, filled with a cluster of thymocytes, increased in number and size and extended from the corticomedullary boundary into the medulla as the insulitis progressed. The development of lymphatic compartments was occasionally accompanied by a regional disappearance between the cortex and medulla. The CD4- and CD8-positive T cells frequently penetrated through the slender lymphatic walls. The epithelial reticular cell layer lining the perivascular spaces was extensively stained with cytokeratin, but the expression of cytokeratin showed an age-dependent decrease. These findings indicate that the occurrence of LYVE-1-expressing lymphatic compartments and the alteration of CCL21 expression in the lymphatics may be involved in defective thymocyte differentiation and migration, and play a significant role in insulitic and diabetic processes.
MeSH Terms
- Aging
- Animals
- Autoimmune Diseases
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Chemokine CCL21
- Chemokines, CC
- Diabetes Mellitus
- Disease Models, Animal
- Epithelial Cells
- Glycoproteins
- Immunohistochemistry
- Islets of Langerhans
- Keratins
- Lymphatic Vessels
- Lymphocyte Activation
- Membrane Glycoproteins
- Membrane Transport Proteins
- Mice
- Mice, Inbred NOD
- Platelet Endothelial Cell Adhesion Molecule-1
- T-Lymphocytes
- Thymus Gland