CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis

Figure 1.Machine learning based analysis indicates that XCL1's α-helix has drastically reduced levels of membrane remodeling activity compared to those of antimicrobial chemokines CCL20 and CXCL4. At left, the mean σ-score for a window size of 30 are projected on the 3D structures of CCL20, CXCL4, and XCL1. Sequences of the helices are shown below each cartoon. At right, each chemokine's full sequence is visualized on a 2D probability map, with helices highlighted by a white box. X axis, amino acid sequence. Y axis, window size. Color, mean σ-score.

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“…Methods used for SAXS experiments and data fitting were based around those that have been previously described 30,[33][34]55 .…”

Section: Saxs Experiments With Model Membranesmentioning

confidence: 99%

Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

et al. 2020

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“…The possible pathobiological role of CXCL4 in brosis of SSc was highly proved in the previous studies [12,54,55]. For example, serum CXCL4 levels were signi cantly increased in SSc and served as a marker of lung brosis [10].…”

Section: Discussionmentioning

confidence: 90%

“…It was also reported that CXCL4 can directly bind to the CXCR3B chemokine receptor isoform or lipoprotein-related protein-1(LRP1) [11]. In patients with SSc, CXCL4 binds DNA into speci c immune complexes that magnify plasmacytoid dendritic cell (pDC) -hyperactivation and produce in ammatory cytokines, which independent of CXCR3 [12]. These data suggest the involvement of CXCL4…”

Section: Introductionmentioning

confidence: 92%

Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis

Jiang

Chen

Yang

et al. 2020

Preprint

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Objective CXCL4, a chemokine with antiangiogenic property, is reported to be involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). We investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, as well as the effect of CXCL4 on endothelial cell dysfunction and angiogenesis disturbance in SSc and the potential signaling.MethodsWe measured the serum CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls. Then, CXCL4 levels were correlated with their clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort including 50 SSc patients, 12 VEDOSS patients, and 80 healthy controls. Moreover, we studied the anti-angiogenesis effects and the underlying signaling of CXCL4 in human umbilical vein endothelial cells (HUVECs) in vitro. ResultsCirculating levels of the CXCL4 were 103.62% higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, and these observations were confirmed in two independent cohorts. CXCL4 levels were closely associated with digital ulcers (DU) and nailfold video capillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were significantly inhibited by recombinant human CXCL4 or SSc derived serum, which reversed by CXCL4 neutralizing antibody, but not CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor‐1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -β or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. Conclusions CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.

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“…PF4 binds to and aggregates polyanions like heparin 26 . We and others have found that PF4 similarly aggregates NETs, physically compacting them, and enhancing their resistance to endogenous and microbial nucleases 27,28 . We speculated that this activity may be, in part, responsible for our previous observation that PF4 enhances survival in murine lipopolysaccharide (LPS) endotoxemia 29 .…”

Section: Introductionmentioning

confidence: 77%

“…In studies designed to investigate the role of neutrophils in the prothrombotic nature of HIT, we observed that PF4, a chemokine known to cross-aggregate polyanions like heparin 26 , also binds to NETs, presumably via the polyanionic backbone of their DNA, causing them to become physically compact. It has recently been shown that PF4-cfDNA complexes form in vivo during systemic sclerosis 28 and it is likely that they also occur during conditions such as sepsis that precipitate both NETosis and platelet degranulation 22 . We have recently shown that PF4 binding enhances NET resistance to lysis by DNase I and microbial nucleases without displacing histones 27 .…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

Gollomp

Sarkar

Seeholzer

et al. 2019

Preprint

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Word Count: 204 Text Word Count: 4622 Figure Count: 7 Reference Count: 81 AbstractSepsis is characterized by multi-organ system dysfunction that occurs due to infection. It is associated with unacceptably high morbidity and mortality and in need of improved therapeutic intervention. Neutrophils play a crucial role in sepsis, releasing neutrophil extracellular traps (NETs) composed of DNA complexed with histones and toxic antimicrobial proteins that ensnare pathogens but also damage host tissues. At presentation, patients likely have a significant NET burden contributing to the multi-organ damage. Therefore, interventions that prevent NET release would likely be ineffective at preventing NET-based injury. Treatments that enhance NET degradation may liberate captured bacteria and toxic NET degradation products (NDPs) and therefore be of limited therapeutic benefit. We propose that interventions that stabilize NETs and sequester NDPs may be protective in sepsis. Platelet factor 4 (PF4, CXCL4) a platelet-associated chemokine, binds and compacts NETs, increasing their resistance to deoxyribonuclease I. A monoclonal antibody, KKO, which binds to PF4-NET complexes, further enhances this resistance.We now show that PF4 increases NET-mediated bacterial capture in vitro, reduces the release of NDPs, and improves outcome in murine models of sepsis. An Fc-modified KKO further enhances deoxyribonuclease resistance, decreases NDP release, and increases survival in these models, supporting a novel NET-targeting approach to improve outcomes in sepsis.

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CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis

Cited by 111 publications

References 63 publications

Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

Contribution to the peripheral vasculopathy and endothelial cell dysfunction by CXCL4 in Systemic Sclerosis

Neutrophil extracellular trap stabilization leads to improved outcomes in murine models of sepsis

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