CXCL13
C-X-C motif chemokine 13 precursor (Angie) (B cell-attracting chemokine 1) (BCA-1) (B lymphocyte chemoattractant) (CXC chemokine BLC) (Small-inducible cytokine B13) [BCA1] [BLC] [SCYB13]
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The CXCR5 (C-X-C motif chemokine receptor 5) is chemokine transmembrane receptor, acting via its ligand CXCL13 and plays a crucial role in controlling the trafficking of inflammatory cells into and from the sub-retinal space, which contributes to the pathogenesis of AMD. We have previously described the genetic ablation of CXCR5 deficiency causes RPE/choroid abnormalities and retinal degeneration (RD) in aged mice. Here we report the transcriptome data (RNA-Seq) of 24 months old CXCR5 knockout (KO) and age-matched C57BL/6 controls (WT). RNA sequencing was performed on the Illumina HiSeq 2500, providing up to 300 GB of sequence information per flow cell. The quality of RNA-seq libraries, RNA intensity were validated by Agilent Technologies Bioanalyzer-2100. The raw datasets contains on average 292,004,59 reads (after trimming 284,862,43 reads) in retina and 272,527,90 reads (after trimming 266,173,11 reads) in choroid samples. The mapped reads showed that a total of 1586 genes in retina and 1462 genes in choroid are differentially expressed in this experiment. The raw datasets were deposited into NCBI Sequence Read Archive (SRA) database and can be accessed via accession number PRJNA588421.
Keywords
- CXCR5
- FastQC
- RNA-Seq
- aging
- choroid
- mice
- retina
- retinal degeneration
Lymph nodes (LN) are secondary lymphoid organs spread throughout the lymphatic system. They function to filter pathogenic material from the lymphatic fluid to maintain the health of the organism. Subcapsular sinus macrophages (SCSM) are among the first-responders within the LN due to their strategic location within the subcapsular sinus region. These macrophages aid the delivery of immune complexes to B cells and follicular dendritic cells (FDC) within the LN. Here we show an increase in SCSM and other macrophage populations within aged LN. However, immune complex uptake by macrophages within LN was not altered with age, nor was immune complex uptake by B cells. LN stromal cell populations, important in immune responses and the localization and survival of leucocytes, were altered in their representation and distribution in aged LN. In particular, FDC regions were decreased in size and had decreased chemokine CXCL13 expression. Furthermore, the retention of immune complexes by FDC was decreased in aged LN at 24 hr post-injection. As FDC are important in the maintenance of germinal centre responses, the decreased retention of immune complex in aged LN may contribute to the reduced germinal centre responses observed in aged mice.
MeSH Terms
- Aging
- Animals
- Female
- Lymph Nodes
- Macrophages
- Mice
- Mice, Inbred C57BL
Keywords
- ageing
- follicular dendritic cells
- lymph node
- macrophages
- stromal cells
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
The roles of microglia and macrophages during neuroinflammation and neurodegenerative diseases remain controversial. To date, at least 2 activations states have been suggested, consisting of a classical response (M1) and the alternative response (M2). Identifying selective biomarkers of microglia that representative their functional activation states may help elucidate disease course and enable a better understanding of repair mechanisms. Two cocktails containing either tumor necrosis factor (TNF)-α, interleukin (IL)-12, and IL-1β (referred to as CKT-1) or IL-13 and IL-4 (referred to CKT-2) were injections into the hippocampus of mice aged 6, 12, or 24 months. Microarray analysis was performed on hippocampal tissue 3 days postinjection. Gene transcripts were compared between CKT-1 versus CKT-2 stimulator cocktails. Several selective transcripts expressed for the CKT-1 included CXCL13, haptoglobin, MARCO, and calgranulin B, whereas a smaller subset of genes was selectively induced by the CKT-2 and consisted of FIZZ1, IGF-1, and EAR 11. Importantly, selective transcripts were induced at all ages by CKT-1, whereas selective gene transcripts induced by CKT-2 decreased with age suggesting an age-related reduction in the IL-4/ IL-13 signaling pathway.
MeSH Terms
- Aging
- Animals
- Central Nervous System
- Hippocampus
- Mice
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Signal Transduction
Lymph nodes (LNs) are among the first sites of tumor metastasis. The expression of chemokines and chemokine receptors in LNs are involved in cancer prognosis and are considered to be good predictors of tumor progression. The main aim of this study was to assess the expression of important, tumor-promoting chemokines and chemokine receptors in LNs of breast cancer patients. LNs were isolated from eighteen women diagnosed with breast cancer. Data were compared between positive and negative LNs. Expression of chemokines and chemokine receptors were determined by quantitative real-time PCR (qRT-PCR) and flow cytometry. Results of qRT-PCR showed that all chemokines, in particular MCP-1, IL-8, SDF-1 and CXCL13, and chemokine receptors CXCR3, CXCR4 and CCR5 showed greater mRNA expression in LN( ) compared to LN(-) samples. However, these differences were not statistically significant. IL-8 and CXCR5 gene transcripts had significantly higher expression in LN( )patients with stage III compared to those with stage II tumors (P value = 0.04). Results of flow cytometry analysis showed a higher, significant presence of CD69( ), CCR5( ) and CD3( )CCR5( ) cells in LN of LN( ) compared to LN(- )breast cancer patients (P value<0.05). Expression of MCP-1 was higher in LN( ) patients, which was near significance (P value = 0.07). Our findings provide additional information on the expression of essential chemokines and chemokine receptors in LN and on their relationships to important prognostic factors in breast cancer. These findings have important implications for immunotherapeutic interventions in the treatment of breast cancer.
MeSH Terms
- Aging
- Breast Neoplasms
- Chemokines
- Female
- Flow Cytometry
- Gene Expression Regulation, Neoplastic
- Humans
- Lymph Nodes
- Lymphatic Metastasis
- Middle Aged
- RNA, Messenger
- Receptors, Chemokine
Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4( )/CD8( ) T cells and a significantly increased number of CD4( )/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRγ additionally disrupted Hexb(-/-) mice. These results suggest that the FcRγ chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13.
MeSH Terms
- Aging
- Animals
- Atrophy
- Autoantibodies
- Autoimmunity
- Cell Death
- Chemokine CXCL13
- Disease Models, Animal
- Disease Progression
- Gangliosidoses, GM2
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Infant
- Macrophage Activation
- Macrophages
- Male
- Mice
- RNA, Messenger
- Receptors, IgG
- Sandhoff Disease
- Thymus Gland
- beta-Hexosaminidase beta Chain
A pivotal role for tertiary lymphoid structures (TLSs) in promoting Ag-specific humoral responses during chronic inflammation is emerging in several autoimmune conditions, including rheumatoid arthritis, Sjogren's syndrome, and autoimmune thyroiditis. However, there is limited evidence on the cellular and molecular mechanisms underlying TLS formation and their contribution to autoimmunity in the pancreas during autoimmune insulitis. In this study, we performed a detailed and comprehensive assessment of the evolution of TLSs during autoimmune insulitis in 126 female NOD mice from 4 to 38 wk of age. We demonstrated that during progression from peri- to intrainsulitis in early diabetic mice, T and B cell infiltration follows a highly regulated process with the formation of lymphoid aggregates characterized by T/B cell segregation, follicular dendritic cell networks, and differentiation of germinal center B cells. This process is preceded by local upregulation of lymphotoxins alpha/beta and lymphoid chemokines CXCL13 and CCL19, and is associated with infiltration of B220( )/IgD( )/CD23( )/CD21(-) follicular B cells expressing CXCR5. Despite a similar incidence of insulitis, late diabetic mice displayed a significantly reduced incidence of fully organized TLSs and reduced levels of lymphotoxins/lymphoid chemokines. Upon development, TLSs were fully functional in supporting in situ autoreactive B cell differentiation, as demonstrated by the expression of activation-induced cytidine deaminase, the enzyme required for Ig affinity maturation and class switching, and the presence of CD138( ) plasma cells displaying anti-insulin reactivity. Overall, our work provides direct evidence that TLSs are of critical relevance in promoting autoimmunity and chronic inflammation during autoimmune insulitis and diabetes in NOD mice.
MeSH Terms
- Aging
- Animals
- Autoantibodies
- B-Lymphocyte Subsets
- Cell Differentiation
- Cell Movement
- Cytidine Deaminase
- Dendritic Cells, Follicular
- Diabetes Mellitus, Type 1
- Disease Progression
- Female
- Germinal Center
- Inflammation
- Insulin-Secreting Cells
- Lymphoid Tissue
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Rabbits
- Rats
- T-Lymphocyte Subsets
Studies in aged mice show that the architecture of B-cell areas appears disrupted and that newly made B cells fail to incorporate into the spleen. These observations may reflect altered migration of immature and mature B cells. Using adoptive transfer, we tested the effect of the aged microenvironment and the intrinsic ability of donor B cells from aged mice to migrate to spleens of intact hosts. Spleens of aged recipients were deficient in attracting young or old donor immature B cells. In contrast, immature and mature B cells maintained an intrinsic ability to migrate to young recipient spleens, except that as the aged immature B cells matured, fewer appeared to enter the recirculating pool. CXCL13 protein, which is necessary for the organization of B-cell compartments, was elevated with age and differences in CXCL13 distribution were apparent. In aged spleens, CXCL13 appeared less reticular, concentrated in patches throughout the follicles, and notably reduced in the MAdCAM-1( ) marginal reticular cells located at the follicular edge. Despite these differences, the migration of young donor follicular B cells into the spleens of old mice was not impacted; whereas, migration of young donor marginal zone B cells was reduced in aged recipients. Finally, the aged bone marrow microenvironment attracted more donor mature B cells than did the young marrow. Message for CXCL13 was not elevated in the marrow of aged mice. These results suggest that the aged splenic microenvironment affects the migration of immature B cells more than mature follicular B cells.
MeSH Terms
- Adoptive Transfer
- Aging
- Animals
- B-Lymphocyte Subsets
- Bone Marrow
- Cell Adhesion Molecules
- Cell Differentiation
- Cell Movement
- Chemokine CXCL13
- Male
- Mice
- Mice, Inbred BALB C
- Mucoproteins
- Precursor Cells, B-Lymphoid
- Spleen
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
Mesenchymal stromal cells are crucial components of secondary lymphoid organs (SLOs). Organogenesis of SLOs involves specialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established a VCAM-1( )ICAM-1( )MAdCAM-1( ) reticular cell line that can produce CXCL13 upon LTbetaR stimulation and support primary B cell adhesion and migration in vitro. A similar stromal population sharing many characteristics with the LTo, designated marginal reticular cells (MRCs), was found in the outer follicular region immediately underneath the subcapsular sinus of lymph nodes. Moreover, MRCs were commonly observed at particular sites in various SLOs even in Rag2(-/-) mice, but were not found in ectopic lymphoid tissues, suggesting that MRCs are a developmentally determined element. These findings lead to a comprehensive view of the stromal composition and architecture of SLOs.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- B-Lymphocytes
- Cell Line
- Cell Line, Tumor
- Cell Movement
- Chemokine CXCL13
- Fibroblasts
- Humans
- Lymphoid Tissue
- Lymphotoxin beta Receptor
- Mesoderm
- Mice
- Mice, Inbred BALB C
- Mice, Mutant Strains
- Protein-Serine-Threonine Kinases
- Signal Transduction
- Stromal Cells
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