Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis

Blokland, Sofie L M; Hillen, Maarten R; Kruize, Aike A.; Meller, Stephan; Homey, Bernhard; Smithson, Glennda; Radstake, Timothy R D J; Roon, Joël A G van

doi:10.1002/art.40182

Cited by 50 publications

(67 citation statements)

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“…In addition, there was a trend towards increased CCL20 expression ( P = .077), and a decrease of CCL27 expression ( P = .050), whereas CCL17 was not differentially expressed (Figure A). As we have previously reported, increased protein levels of CCL25 and CXCL10 in secretomes of pSS salivary gland tissue were observed . We here report that upregulated CCL25 mRNA expression significantly correlated to CXCL10 (Figure C).…”

Section: Resultssupporting

confidence: 87%

“…Next we assessed whether mRNA and protein expression of representative chemokines that can attract CXCR3, CCR4, CCR6 and CCR10‐expressing Th cells were expressed by salivary gland tissue, either expressed as mRNA in tissue lysates or protein levels in supernatant of tissue explants . We previously reported that mRNA expression of CCL25 was significantly increased in salivary glands of pSS patients as compared to non‐SS patients . Increased CXCL10 mRNA expression as previously reported by others was confirmed (Figure A).…”

Section: Resultssupporting

confidence: 73%

“…Since a decrease of CXCR3 + CCR9 + Th cells was found in the circulation of pSS patients and both CCL25 and CXCL10 showed the strongest increased expression in the salivary glands on both mRNA and protein level (Figure A and ), the chemotactic capacity of CXCL10 in combination with CCL25 was investigated. In a transwell system, chemotaxis of Th cells in response to different concentrations of CCL25 and CXCL10 was assessed.…”

Section: Resultsmentioning

confidence: 99%

“…Several chemokines and receptors have been shown to be upregulated in the salivary and lacrimal glands of pSS patients potentially leading to migration of T cells to the glands, including the interferon‐induced chemokines CXCL9, CXCL10, CXCL11 and their receptor CXCR3 . Recently, CXCR5 + T follicular helper (Tfh) cells and their ligand CXCL13 and CCR9+ ‘Tfh‐like’ cells with their ligand CCL25 have been implicated in disease pathogenesis . Both levels of CXCL13 and CCL25 and numbers of CXCR5 + and CCR9 + Th cells are elevated in the salivary glands of pSS patients.…”

Section: Introductionmentioning

confidence: 99%

“…Both levels of CXCL13 and CCL25 and numbers of CXCR5 + and CCR9 + Th cells are elevated in the salivary glands of pSS patients. CXCR5 + Tfh and CCR9 + Tfh‐like cells produce pro‐inflammatory cytokines and provide co‐stimulatory signals that strongly stimulate B cell responses which play an important role in B cell hyperactivity pSS . In addition, these Tfh and Tfh‐like cells may be involved in the formation of germinal centre‐like structures, which are present in the salivary glands of ~25% of pSS patients .…”

Section: Introductionmentioning

confidence: 99%

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Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

et al. 2019

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CCR9 + T helper (Th) cells can induce Sjögren‐like symptoms in mice and both CCR9 + Th cells and their ligand CCL25 are increased in the salivary glands of primary Sjögren's syndrome (pSS) patients. Increased circulating CCR9 + Th cells are present in pSS patients. CCR9 + Th cells are hyperresponsive to IL‐7, secrete high levels of IFN‐γ, IL‐21, IL‐17 and IL‐4 and potently stimulate B cells in both patients and healthy individuals. Our aim was to study co‐expression of chemokine receptors on CCR9 + Th cells and whether in pSS this might differentially affect CCR9 + Th cell frequencies. Frequencies of circulating CCR9 + and CCR9‐ Th cells co‐expressing CXCR3, CCR4, CCR6 and CCR10 were studied in pSS patients and healthy controls. CCL25, CXCL10, CCL17, CCL20 and CCL27 mRNA and protein expression of salivary gland tissue of pSS and non‐Sjögren's sicca (non‐SS) patients was assessed. Chemotaxis assays were performed to study migration induced by CXCL10 and CCL25. Higher expression of CXCR3, CCR4 and CCR6 but not CCR10 was observed on CCR9 + Th cells as compared to cells lacking CCR9. Decreased frequencies of circulating memory CCR9 + CXCR3+ Th cells were found in pSS patients, which was most pronounced in the effector memory subset. Increased salivary gland CCL25 and CXCL10 expression significantly correlated and both ligands functioned synergistically based on in vitro induced chemotaxis. Decreased memory CXCR3 + CCR9+ Th cells in blood of pSS patients may be due to a concerted action of overexpressed ligands at the site of inflammation in the salivary glands facilitating their preferential migration and positioning in the lymphocytic infiltrates.

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Section: Resultssupporting

confidence: 87%

Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

et al. 2019

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Interleukin‐7/Interferon Axis Drives T Cell and Salivary Gland Epithelial Cell Interactions in Sjögren’s Syndrome

Rivière

Pascaud

Virone

et al. 2021

Arthritis & Rheumatology

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Objective. Primary Sjögren's syndrome (SS) is characterized by a lymphocytic infiltration of salivary glands (SGs) and the presence of an interferon (IFN) signature. SG epithelial cells (SGECs) play an active role in primary SS pathophysiology. We undertook this study to examine the interactions between SGECs and T cells in primary SS and the role of the interleukin-7 (IL-7)/IFN axis. Methods. Primary cultured SGECs from control subjects and patients with primary SS were stimulated with poly(I-C), IFNα, or IFNγ. T cells were sorted from blood and stimulated with IL-7. CD25 expression was assessed by flow cytometry. SG explants were cultured for 4 days with anti-IL-7 receptor (IL-7R) antagonist antibody (OSE-127), and transcriptomic analysis was performed using the NanoString platform. Results. Serum IL-7 level was increased in patients with primary SS compared to controls and was associated with B cell biomarkers. IL7R expression was decreased in T cells from patients with primary SS compared to controls. SGECs stimulated with poly(I-C), IFNα, or IFNγ secreted IL-7. IL-7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of SG explants showed a correlation between IL7 and IFN expression. Finally, explants cultured with anti-IL-7R antibody showed decreased IFN-stimulated gene expression. Conclusion. These results suggest the presence of an IL-7/IFNγ amplification loop involving SGECs and T cells in primary SS. IL-7 was secreted by SGECs stimulated with type I or type II IFN and, in turn, activated T cells that secrete type II IFN. An anti-IL-7R antibody decreased the IFN signature in T cells in primary SS and could be of therapeutic interest.

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CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts

et al. 2021

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This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL‐1β and IL‐6. CCR9 is also presented on IL‐1β and IL‐6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3‐month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25‐stimulated RA FLS secrete potentiated levels of IL‐8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL‐8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25‐induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25‐induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF‐α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation.

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Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis

Cited by 50 publications

References 51 publications

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

Decreased circulating CXCR3 + CCR9+T helper cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with Sjögren’s syndrome to facilitate their concerted migration

Interleukin‐7/Interferon Axis Drives T Cell and Salivary Gland Epithelial Cell Interactions in Sjögren’s Syndrome

CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts

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