Pro-Fibrotic Effects of CCL18 on Human Lung Fibroblasts Are Mediated via CCR6

Höhne, Kerstin; Wagenknecht, Annett; Maier, Corinna; Engelhard, Peggy; Goldmann, Torsten; Schließmann, Stephan J.; Plönes, Till; Trepel, Martin; Eibel, Hermann; Müller-Quernheim, Joachim; Zissel, Gernot

doi:10.3390/cells13030238

Cited by 3 publications

(1 citation statement)

References 59 publications

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“…Moreover, CCL18 was seen to be expressed in atherosclerotic plaques, particularly in areas of decreased stability ( 10 ), where it co-localizes with CD83+ dendritic cells. For long viewed as orphan ligand, CCL18 was recently proposed not only to be a competitive inhibitor of CCL11 (eotaxin) binding to chemokine receptor 3 (CCR3) ( 11 ) but also to bind to CCR8 ( 12 ), phosphatidylinositol transfer protein 3 (PITPNM3) ( 13 ), nitrite reductase 1 (NIR1) ( 14 ), and CCR6 ( 15 ), although a subsequent study failed to confirm this link ( 16 ). CCL18 is produced by monocyte subsets and naïve CD4 + T cells and able to stimulate collagen production by fibroblasts ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

Singh,

Kraaijeveld,

Curaj

et al. 2024

Front. Immunol.

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IntroductionThe CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis.Methods and resultsCCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet–fed ApoE−/− mice or PCSK9mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6−/− mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6’s role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells.DiscussionOur studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

Singh,

Kraaijeveld,

Curaj

et al. 2024

Front. Immunol.

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Altered AP-1, RUNX and EGR chromatin dynamics drive fibrotic lung disease

Valenzi,

Jia,

Gerges

et al. 2024

Preprint

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Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1hi macrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs. The neural network tool ChromBPNet inferred increased TF binding at single base pair resolution to profibrotic genes, including CTHRC1 and ADAM12, in fibroblasts and SPP1 and CCL18 in macrophages. The novel algorithm HALO confirmed AP-1, RUNX, and EGR TF activity controlling profibrotic gene programs and established TF-regulatory element-gene networks. This TF action atlas provides comprehensive insights into the transcriptional regulation of fibroblasts and macrophages in healthy and fibrotic human lungs.

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The Laws of Attraction: Chemokines as Critical Mediators in Cancer Progression and Immunotherapy Response in Bladder Cancer

Hassouneh,

Kim,

Bowman

et al. 2024

Cancers

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Bladder cancer (BCa) is a prevalent urogenital malignancy, characterized by a myriad of genetic and environmental risk factors that drive its progression. Approximately 75% of bladder tumors are non-muscle-invasive at diagnosis. For such cases, bladder preservation is often feasible with intravesical chemotherapy or immunotherapy. However, the high recurrence rates associated with these tumors necessitate multiple cystoscopic examinations and biopsies, leading to significant financial burden and morbidity. Despite bladder tumors exhibiting one of the highest cancer mutational loads, which typically correlates with improved responses to immunotherapy, challenges persist. The tumor microenvironment serves as a nexus for interactions between tumor cells and the immune system, wherein chemokines and chemokine receptors orchestrate the recruitment of immune cells. This review addresses existing gaps in our understanding of chemokine dynamics in BCa by elucidating the specific roles of key chemokines in shaping the immune landscape of the tumor microenvironment (TME). We explore how dysregulation of chemokine signaling pathways contributes to the recruitment of immunosuppressive cell populations, such as Tregs and monocytes, leading to an unfavorable immune response. Additionally, we highlight the potential of these chemokines as predictive biomarkers for tumor progression and treatment outcomes, emphasizing their role in informing personalized immunotherapeutic strategies. By integrating insights into chemokine networks and their implications for immune cell dynamics, this review seeks to provide a comprehensive understanding of the interplay between chemokines and the immune microenvironment in BCa. Furthermore, we discuss the potential of targeting these chemokine pathways as innovative immunotherapeutic strategies, paving the way for enhanced treatment responses and improved patient outcomes.

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Pro-Fibrotic Effects of CCL18 on Human Lung Fibroblasts Are Mediated via CCR6

Cited by 3 publications

References 59 publications

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

Altered AP-1, RUNX and EGR chromatin dynamics drive fibrotic lung disease

The Laws of Attraction: Chemokines as Critical Mediators in Cancer Progression and Immunotherapy Response in Bladder Cancer

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