CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-β/Smad signaling

Wang, Qian-rong; Liu, Suo-si; Min, Jiali; Yin, Min; Zhang, Yan; Tang, Xiang-ning; Li, Xia; Liu, Shanshan

doi:10.1016/j.bcp.2023.115475

Cited by 8 publications

(4 citation statements)

References 45 publications

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“…CIB1 knockdown reduces intracellular tension‐derived stress, leading to the downregulation of inflammatory response, including the expression of CCL22. Interestingly, this cytokine interacts with CC chemokine receptor 4 (CCR4), which is the receptor of CCL22 and CCL17 (Scheu et al, 2017) in fibroblasts and endothelial cells (Flytlie et al, 2010; Wang et al, 2023). CCR4 activation triggers TGF‐β/Smad signaling pathway, contributing to tissue fibrosis (Wang et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, this cytokine interacts with CC chemokine receptor 4 (CCR4), which is the receptor of CCL22 and CCL17 (Scheu et al, 2017) in fibroblasts and endothelial cells (Flytlie et al, 2010; Wang et al, 2023). CCR4 activation triggers TGF‐β/Smad signaling pathway, contributing to tissue fibrosis (Wang et al, 2023). Although previous studies have reported upregulation of chemokines and cytokines in liver cirrhosis, this is the first time to our knowledge that a CIB1‐dependent stiffness‐induced modulation of CCL22 is observed in LSECs.…”

Section: Discussionmentioning

confidence: 99%

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Role of calcium integrin‐binding protein 1 in the mechanobiology of the liver endothelium

Wang,

Felli,

Selicean

et al. 2024

Journal Cellular Physiology

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Liver sinusoidal endothelial cells (LSECs) dysfunction is a key process in the development of chronic liver disease (CLD). Progressive scarring increases liver stiffness in a winch‐like loop stimulating a dysfunctional liver cell phenotype. Cellular stretching is supported by biomechanically modulated molecular factors (BMMFs) that can translocate into the cytoplasm to support mechanotransduction through cytoskeleton remodeling and gene transcription. Currently, the molecular mechanisms of stiffness‐induced LSECs dysfunction remain largely unclear. Here we propose calcium‐ and integrin‐binding protein 1 (CIB1) as BMMF with crucial role in LSECs mechanobiology in CLD. CIB1 expression and translocation was characterized in healthy and cirrhotic human livers and in LSECs cultured on polyacrylamide gels with healthy and cirrhotic‐like stiffnesses. Following the modulation of CIB1 with siRNA, the transcriptome was scrutinized to understand downstream effects of CIB1 downregulation. CIB1 expression is increased in LSECs in human cirrhosis. In vitro, CIB1 emerges as an endothelial BMMF. In human umbilical vein endothelial cells and LSECs, CIB1 expression and localization are modulated by stiffness‐induced trafficking across the nuclear membrane. LSECs from cirrhotic liver tissue both in animal model and human disease exhibit an increased amount of CIB1 in cytoplasm. Knockdown of CIB1 in LSECs exposed to high stiffness improves LSECs phenotype by regulating the intracellular tension as well as the inflammatory response. Our results demonstrate that CIB1 is a key factor in sustaining cellular tension and stretching in response to high stiffness. CIB1 downregulation ameliorates LSECs dysfunction, enhancing their redifferentiation, and reducing the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of calcium integrin‐binding protein 1 in the mechanobiology of the liver endothelium

Wang,

Felli,

Selicean

et al. 2024

Journal Cellular Physiology

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“…Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate pulmonary fibrosis pathology in mice. The study showed that CCL17 is a profibrotic mediator of lung fibroblasts, suggesting that CCL17 or CCR4 inhibition may serve as an effective strategy to suppress lung fibroblast activation and attenuate pulmonary fibrosis progression [132].…”

Section: Cytokines/chemokinesmentioning

confidence: 99%

Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways

Pokhreal,

Crestani,

Helou

2023

Cells

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Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease of unknown etiology with a poor prognosis. It is a chronic and progressive disease that has a distinct radiological and pathological pattern from common interstitial pneumonia. The use of immunosuppressive medication was shown to be completely ineffective in clinical trials, resulting in years of neglect of the immune component. However, recent developments in fundamental and translational science demonstrate that immune cells play a significant regulatory role in IPF, and macrophages appear to be among the most crucial. These highly plastic cells generate multiple growth factors and mediators that highly affect the initiation and progression of IPF. In this review, we will provide an update on the role of macrophages in IPF through a systemic discussion of various regulatory mechanisms involving immune receptors, cytokines, metabolism, and epigenetics.

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“…S100A9 and S100A12 serve as biomarkers for neutrophilic asthma [51,52]. CCL17 is associated with asthma and may contribute to airway remodelling through fibroblast activation via the CCR4-CCL17 axis [53,54]. S1PR5 regulates monocyte trafficking [55], suggesting intermediate monocytes from asthmatic horses may possess a higher migratory capacity.…”

Section: Genes Associated With T-cell Function Are Dysregulated In Seamentioning

confidence: 99%

Single‐cell profiling of bronchoalveolar cells reveals a Th17 signature in neutrophilic severe equine asthma

Sage,

Leeb,

Jagannathan

et al. 2023

Immunology

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Severe equine asthma (SEA) is a complex respiratory condition characterized by chronic airway inflammation. It shares many clinical and pathological features with human neutrophilic asthma, making it a valuable model for studying this condition. However, the immune mechanisms driving SEA have remained elusive. Although SEA has been primarily associated with a Th2 response, there have also been reports of Th1, Th17, or mixed‐mediated responses. To uncover the elusive immune mechanisms driving SEA, we performed single‐cell mRNA sequencing (scRNA‐seq) on cryopreserved bronchoalveolar cells from 11 Warmblood horses, 5 controls and 6 with SEA. We identified six major cell types, including B cells, T cells, monocytes–macrophages, dendritic cells, neutrophils, and mast cells. All cell types exhibited significant heterogeneity, with previously identified and novel cell subtypes. Notably, we observed monocyte–lymphocyte complexes and detected a robust Th17 signature in SEA, with CXCL13 upregulation in intermediate monocytes. Asthmatic horses exhibited expansion of the B‐cell population, Th17 polarization of the T‐cell populations, and dysregulation of genes associated with T‐cell function. Neutrophils demonstrated enhanced migratory capacity and heightened aptitude for neutrophil extracellular trap formation. These findings provide compelling evidence for a predominant Th17 immune response in neutrophilic SEA, driven by dysregulation of monocyte and T‐cell genes. The dysregulated genes identified through scRNA‐seq have potential as biomarkers and therapeutic targets for SEA and provide insights into human neutrophilic asthma.

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CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-β/Smad signaling

Cited by 8 publications

References 45 publications

Role of calcium integrin‐binding protein 1 in the mechanobiology of the liver endothelium

Role of calcium integrin‐binding protein 1 in the mechanobiology of the liver endothelium

Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways

Single‐cell profiling of bronchoalveolar cells reveals a Th17 signature in neutrophilic severe equine asthma

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