CCL26 and CCR3 are associated with the acute inflammatory response in the CNS in experimental autoimmune encephalomyelitis

Shou, Jifei; Peng, Jing; Zhao, Zhikang; Huang, Xiaoxi; Li, Hui; Li, Liheng; Gao, Xinxin; Xing, Yanmeng; Liu, Hongbo

doi:10.1016/j.jneuroim.2019.576967

Cited by 14 publications

(9 citation statements)

References 39 publications

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“…In addition to binding to CCR3, CCL26 also binds to CX3CR1, thereby accumulating not only CX3CR1-expressing cells, such as terminally differentiated CD16 + natural killer cells and CD8 + T cells, but also CCR3-expressing cells, such as Th2 cells, eosinophils and mast cells (32). Similarly, it was found that CCL26 promoted the expression of CX3CR1 in the PBMCs of patients with AIS, suggesting the involvement of CCL26/CX3CR1 in the immune response during AIS.…”

Section: Discussionmentioning

confidence: 91%

CCL26 regulates the proportion of CD4+CD25+FOXP3+�Tregs and the production of inflammatory factors in peripheral blood mononuclear cells following acute ischemic stroke via the STAT5 pathway

et al. 2020

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Acute ischemic stroke (AIS) is the most common type of stroke. Recent studies have found that AIS is closely involved in the immune regulation function of regulatory T cells (Tregs). CC motif chemokine ligand 26 (CCL26) is a member of the chemokine family that plays an essential role in cell activation, cell differentiation, lymphocyte homing, and inflammatory and immune responses. The present study aimed to investigate the role of CCL26 in the regulation of Tregs in AIS. Peripheral blood mononuclear cells (PBMCs) were incubated with a CCL26-neutralizing antibody. The proportion of cluster of differentiation (CD)4 + CD25 + forkhead box P3 (FOXP3) + Tregs was increased, and the expression of FOXP3, phosphorylated signal transducer and activator of transcription 5 (p-STAT5), and that of the immunosuppressive factors, interleukin (IL)-10 and transforming growth factor (TGF)-β1, was upregulated. Conversely, the expression of immune-promoting factors, such as tumor necrosis factor (TNF)-α and IL-6 was significantly downregulated. Further experiments using CCL26 recombinant protein-treated PBMCs revealed a decreased proportion of CD4 + CD25 + FOXP3 + Tregs and the downregulated expression of FOXP3, p-STAT5, TGF-β1 and IL-10. Moreover, the expression of immunostimulatory factors, such as CX3C chemokine receptor 1, TNF-α and IL-6 was significantly upregulated. On the whole, these results demonstrate that CCL26 regulates the proportion of CD4 + CD25 + FOXP3 + Tregs and the production of inflammatory factors in PBMCs following AIS via the STAT5 pathway.

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Section: Discussionmentioning

confidence: 91%

CCL26 regulates the proportion of CD4+CD25+FOXP3+�Tregs and the production of inflammatory factors in peripheral blood mononuclear cells following acute ischemic stroke via the STAT5 pathway

et al. 2020

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“…Other genes affecting immune profiles identified in this study include reductions in markers of reparative macrophage polarization CD163 antigen, CD209b antigen and FOLR2 (27,28); the CCR3 ligand eotaxin-2 (CCL24) (29); the macrophage expressed perforin-2 ( Mpeg1 ), a bacterial cell wall pore-forming protein with roles in innate immunity (30); and increased expression of the negative regulator of macrophage inflammation GPNMB (31).…”

Section: Discussionmentioning

confidence: 95%

Transcriptome analysis of the NR1H3 mouse model of multiple sclerosis reveals a pro-inflammatory phenotype with dysregulation of lipid metabolism and immune response genes

Vilariño‐Güell

Encarnacion

et al. 2021

Preprint

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BackgroundThe development of effective treatments for multiple sclerosis (MS), and in particular its progressive forms, is hampered by the lack of etiologically relevant cellular and animal models of human disease. Models that recapitulate the biological and pathological processes leading to the onset and progression of MS in patients are likely to afford better translational efficacy. Following the discovery of the NR1H3 p.Arg415Gln pathogenic mutation for progressive MS in two Canadian families, we developed a knock-in mouse model harboring a homologous mutation in the endogenous gene to provide a more physiologically relevant model of human MS.MethodsGene expression was evaluated in constitutive heterozygote (which recapitulates the human disease genotype) and homozygote Nr1h3 p.Arg413Gln knock-in mice on a C57BL/6 background, and compared to wild-type littermates. AmpliSeq Transcriptome Mouse Gene Expression kits analyzed on an Ion Proton sequencer were used to generate the gene expression profiles of spleen, liver, brain and spinal cord tissue from three-month-old male and female mice. Differential expression between genotypes was assessed with DESeq2, and Gene Ontologies pathways enrichment analysis performed with DAVID v6.8. Benjamini-Hochberg false discovery rate (FDR) correction for multiple testing was applied.ResultsTranscriptome analysis of spleen tissue from Nr1h3 p.Arg413Gln mice revealed 23 significantly dysregulated genes (FDR<0.05) with greater than a two-fold change in expression. These include CD5 antigen-like (Cd5l), complement component 6 (C6), procollagen C-endopeptidase enhancer 2 (Pcolce2), interleukin 22 receptor, alpha 2 (Il22ra2), and T cell immunoglobulin and mucin domain containing 4 (Timd4). Gene Ontology enrichment analysis support upregulation of cell cycle pathways and downregulation of immune system response in splenic cells. The liver transcriptome identified 27 significantly dysregulated genes with greater than a two-fold change in expression compared to wild-type littermates. Cd5l, Timd4, C-C motif chemokine receptor 3 (Ccr3), ADAM metallopeptidase domain 11 (Adam11) and macrophage expressed 1 (Mpeg1) were amongst those most significantly dysregulated. Enrichment analysis supported altered immune function with upregulation of sterol and steroid metabolic processes and downregulation of fatty acid biosynthesis and inflammatory and immune system responses. Although brain and spinal cord transcriptome profiles identified several genes significantly dysregulated in Nr1h3 mice compared to wild-type littermates (FDR<0.05), none presented greater than two-fold changes in gene expression.DiscussionThe analysis of the Nr1h3 p.Arg413Gln mouse model of MS suggests that the predominance of a pro-inflammatory over a healing or reparative phenotype, combined with deficiencies in myelination and remyelination, are the biological mechanisms implicated in the onset of MS and the development of a more severe progressive disease course observed in patients with NR1H3 mutations. Association of NR1H3 common variants with MS risk indicates that the disruption of these biological and immunological processes is not only informative for familial forms of disease but MS patients at large. Differences in transcriptome profiles underline the value of this model for the development and validation of novel therapeutic strategies and ultimately treatments with the potential to delay or even halt the onset of progressive MS and to ameliorate the severity of clinical symptoms.

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“…CCL26 is a ligand of the CCR3 receptor that controls various signals, including Rac, Src, FAK, PI3K, and ERK 9 – 12 . Normally, CCL26 plays a role in eosinophil migration during allergies, but we speculated that it might also be involved in the cell migration and motility of cancer cells 24 , 25 . Our research focused in particular on Rac and Src and their associated pathways because they represent factors associated with the motility downstream of CCR3.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the signal cross talk via CCL26 in the tumor microenvironment in osteosarcoma

Kawano

Iwasaki

Itonaga

et al. 2021

Sci Rep

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Interaction with surrounding healthy cells plays a major role in the growth and metastasis of osteosarcoma. In this study, we hypothesized that humoral factors, which do not require direct contact with cells, are involved in the interaction between osteosarcoma and the surrounding cells. We identified the humoral factor involved in the association between tumor cells and surrounding normal cells using a co-culture model and investigated the significance of our findings. When human osteosarcoma cells (MG63) and human mesenchymal stem cells (hMSCs) were co-cultured and comprehensively analyzed for changes in each culture group, we found that the expression of chemokine (CC motif) ligand 26 (CCL26) was significantly enhanced. We also analyzed the changes in cell proliferation in co-culture, enhanced interaction with administration of recombinant CCL26 (rCCL26), reduced interaction with administration of anti-CCL26 antibodies, changes in invasive and metastatic abilities. CCL26 levels, motility, and invasive capability increased in the co-culture group and the group with added rCCL26, compared to the corresponding values in the MG63 single culture group. In the group with added CCL26 neutralizing antibodies, CCL26 level decreased in both the single and co-culture groups, and motility and invasive ability were also reduced. In a nude mice lung metastasis model, the number of lung metastases increased in the co-culture group and the group with added rCCL26, whereas the number of tumors were suppressed in the group with added neutralizing antibodies compared to those in the MG63 alone. This study identified a possible mechanism by which osteosarcoma cells altered the properties of normal cells to favorably change the microenvironment proximal to tumors and to promote distant metastasis.

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CCL26 and CCR3 are associated with the acute inflammatory response in the CNS in experimental autoimmune encephalomyelitis

Cited by 14 publications

References 39 publications

CCL26 regulates the proportion of CD4+CD25+FOXP3+�Tregs and the production of inflammatory factors in peripheral blood mononuclear cells following acute ischemic stroke via the STAT5 pathway

CCL26 regulates the proportion of CD4+CD25+FOXP3+�Tregs and the production of inflammatory factors in peripheral blood mononuclear cells following acute ischemic stroke via the STAT5 pathway

Transcriptome analysis of the NR1H3 mouse model of multiple sclerosis reveals a pro-inflammatory phenotype with dysregulation of lipid metabolism and immune response genes

Analysis of the signal cross talk via CCL26 in the tumor microenvironment in osteosarcoma

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