CXCL4 drives fibrosis by promoting several key cellular and molecular processes

Affandi, Alsya J.; Carvalheiro, Tiago; Ottria, Andrea; Haan, Judith J. de; Brans, Maike A.D.; Brandt, Maarten M.; Tieland, Ralph G.; Lopes, Ana P; Fernández, Beatriz; Bekker, Cornelis P. J.; Linden, Maarten van der; Zimmermann, Maili; Giovannone, Barbara; Wichers, Catharina G K; García, Samuel; Kok, Michael de; Stifano, Giuseppina; Xu, Yan; Kowalska, M. Anna; Waasdorp, Maaike; Cheng, Caroline; Gibbs, Susan; Jager, Saskia C.A. de; Roon, Joël A G van; Radstake, Timothy R D J; Marut, Wioleta

doi:10.1016/j.celrep.2021.110189

Cited by 45 publications

(30 citation statements)

References 96 publications

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“…CXCL4 has been validated to stimulate endothelial-to-mesenchymal transition in fibrotic tissues. Myofibroblast differentiation and collagen synthesis are directly induced, indicating that CXCL4 may be a potential therapeutic target for the treatment of fibrosis and scars [ 55 ]. Meanwhile, N-cadherin has been shown to be critical in injury-triggered swarming, as well as migration of fascia fibroblasts that progressively contract the skin and form scars [ 56 ].…”

Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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Scarring, which develops due to fibroblast activation and excessive extracellular matrix deposition, can cause physical, psychological, and cosmetic problems. Fibroblasts are the main type of connective tissue cells and play important roles in wound healing. However, the underlying mechanisms of fibroblast in reaching scarless wound healing require more exploration. Herein, we systematically reviewed how fibroblasts behave in response to skin injuries, as well as their functions in regeneration and scar formation. Several biocompatible materials, including hydrogels and nanoparticles, were also suggested. Moreover, factors that concern transformation from fibroblasts into cancer-associated fibroblasts are mentioned due to a tight association between scar formation and primary skin cancers. These findings will help us better understand skin fibrotic pathogenesis, as well as provide potential targets for scarless wound healing therapies.

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Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Using the bleomycin (BLM)-induced skin fibrosis model, we have reported that pDCs are key players in the establishment and maintenance of skin fibrosis ( Ah Kioon et al, 2018 ). In addition, we observed that CXCL4 is induced in the skin of the BLM-treated mice ( Ah Kioon et al, 2018 ), and it was recently shown that CXCL4-deficient mice do not progress to fibrosis in BLM-treated mice ( Affandi et al, 2022 ). Hence, in this model, the CXCL4 is endogenously produced and associated with disease.…”

Section: Resultsmentioning

confidence: 93%

Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation

Kioon

Laurent

et al. 2022

Journal of Experimental Medicine

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Chemokines control the migratory patterns and positioning of immune cells to organize immune responses to pathogens. However, many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signatures. We report that a series of chemokines, including CXCL4, CXCL10, CXCL12, and CCL5, can superinduce type I IFN (IFN-I) by TLR9-activated plasmacytoid DCs (pDCs), independently of their respective known chemokine receptors. Mechanistically, we show that chemokines such as CXCL4 mediate transcriptional and epigenetic changes in pDCs, mostly targeted to the IFN-I pathways. We describe that chemokines physically interact with DNA to form nanoparticles that promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two separate mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data reveal a noncanonical role for chemokines to serve as nucleic acid delivery vectors to modulate TLR signaling, with implications for the chronic presence of IFN-I by pDCs in autoimmune diseases.

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“…CD14, which is engaged in toll-like receptor signaling by LPS, is expressed by these cells at high levels (Figure 2C, Figure S3B). Cluster 4 expresses transcripts involved in fibrosis, including Pf4, CD206, and Stab1 (Fig S3C) (14)(15)(16)(17)(18). Cluster 5 can be distinguished by the expression of Vim, Ccl2, Tnip3, and Ccr2 transcripts (Figure 2C, Figure S3D).…”

Section: Delineation Of Transcriptionally Distinct Kidney Resident Ma...mentioning

confidence: 99%

Resident macrophage subpopulations occupy distinct microenvironments in the kidney

Cheung¹,

Erman²,

Moore³

et al. 2022

JCI Insight

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The kidney contains a population of resident macrophages from birth that expands as it grows and forms a contiguous network throughout the tissue. Kidney-resident macrophages (KRMs) are important in homeostasis and the response to acute kidney injury. While the kidney contains many microenvironments, it is unknown whether KRMs are a heterogeneous population differentiated by function and location. We combined single-cell RNA-Seq (scRNA-Seq), spatial transcriptomics, flow cytometry, and immunofluorescence imaging to localize, characterize, and validate KRM populations during quiescence and following 19 minutes of bilateral ischemic kidney injury. scRNA-Seq and spatial transcriptomics revealed 7 distinct KRM subpopulations, which are organized into zones corresponding to regions of the nephron. Each subpopulation was identifiable by a unique transcriptomic signature, suggesting distinct functions. Specific protein markers were identified for 2 clusters, allowing analysis by flow cytometry or immunofluorescence imaging. Following injury, the original localization of each subpopulation was lost, either from changing locations or transcriptomic signatures. The original spatial distribution of KRMs was not fully restored for at least 28 days after injury. The change in KRM localization confirmed a long-hypothesized dysregulation of the local immune system following acute injury and may explain the increased risk for chronic kidney disease.

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CXCL4 drives fibrosis by promoting several key cellular and molecular processes

Cited by 45 publications

References 96 publications

Fibroblasts in Scar Formation: Biology and Clinical Translation

Fibroblasts in Scar Formation: Biology and Clinical Translation

Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation

Resident macrophage subpopulations occupy distinct microenvironments in the kidney

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