CX3CL1–CX3CR1 interaction mediates macrophage-mesothelial cross talk and promotes peritoneal fibrosis

Helmke, Alexandra; Nordlohne, Johannes; Balzer, Michael S.; Dong, Lei; Rong, Song; Hiß, Marcus; Shushakova, Nelli; Haller, Hermann; Vietinghoff, Sibylle von

doi:10.1016/j.kint.2018.12.030

Cited by 49 publications

(39 citation statements)

References 51 publications

(81 reference statements)

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“…To address the concern and to merit the value of current model, we showed in vitro that hypochlorite-induced damages likely restricted to chemical and mechanical disruption of mesothelial cells rather than initiation of complex signal cascades for programmed death as we demonstrated in vitro that hypochlorite induced necrosis, but not apoptosis of the mesothelial cells (MeT-5A); moreover increased inflammatory cytokines IL-1β and TNF-α was measured from NaOCl-injured pigs; as NaOCl was administrated via intraperitoneal injection, a direct contact of peritoneal mesothelium with NaOCl in in vivo model likely resulted in massive necrosis as observed in in vitro assay. Moreover, overexpression of fractalkine CX3CL1 and TGFβ1 on the surface of the both parietal and visceral mesothelium observed in this study was likely due to the stimulation of IL-1β as observed in our study and was described earlier by Helmke et al 23 . The subsequent overexpression and release of TGFβ1 from the mesothelium was evidenced from our time point immunofluorescent data and enzyme-linked immunoabsorbent assay (ELISA) analysis of peritoneal lavage.…”

Section: Discussionsupporting

confidence: 86%

“…Recent publication suggested fractalkine receptor (CX3CR1)-CX3CL1 interaction mediated macrophage-mesothelium crosstalk and promoted PD-induced peritoneal fibrosis 23 . To study whether NaClO-induced PF shares similar signal transduction and pathogenesis as those of PD-induced PF, we evaluated mesothelium expression of cell surface CX3CL1 from 0.1% NaClO-injured pigs.…”

Section: Resultsmentioning

confidence: 99%

“…Recent study by Helmke et al showed CX3CL1-CX3CR1 interaction mediates macrophage-mesothelial cross talk and was responsible for PD-induced peritoneal fibrosis 23 Although hypochlorite is a fast and efficient method to induce PF; however, its molecular and cellular mechanisms were not fully understood and was considered as a “non-clinical relevant” approach to re-create PF in human patients. To address the concern and to merit the value of current model, we showed in vitro that hypochlorite-induced damages likely restricted to chemical and mechanical disruption of mesothelial cells rather than initiation of complex signal cascades for programmed death as we demonstrated in vitro that hypochlorite induced necrosis, but not apoptosis of the mesothelial cells (MeT-5A); moreover increased inflammatory cytokines IL-1β and TNF-α was measured from NaOCl-injured pigs; as NaOCl was administrated via intraperitoneal injection, a direct contact of peritoneal mesothelium with NaOCl in in vivo model likely resulted in massive necrosis as observed in in vitro assay.…”

Section: Discussionmentioning

confidence: 99%

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Hypochlorite-induced porcine model of peritoneal fibrosis through the activation of IL1β-CX3CL1-TGFβ1 signal axis

Hsu

Chao

et al. 2020

Sci Rep

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Patients with kidney failure rely on life-saving peritoneal dialysis to facilitate waste exchange and maintain homeostasis of physical conditions. However, peritoneal dialysis often results in peritoneal fibrosis and organ adhesion that subsequently compromise the efficiency of peritoneal dialysis and normal functions of visceral organs. Despite rodent models provide clues on the pathogenesis of peritoneal fibrosis, no current large animal model which shares high degree of physiological and anatomical similarities to human is available, limiting their applications on the evaluation of pre-clinical therapeutic efficacy. Here we established for the first time, hypochlorite-induced porcine model of peritoneal fibrosis in 5-week-old piglets. We showed that administration 15–30 mM hypochlorite, a dose- and time-dependent severity of peritoneal fibrosis characterized by mesothelium fragmentation, αSMA + myofibroblasts accumulation, organ surface thickening and type I collagen deposition were observed. We also demonstrated in vitro using human mesothelial cells that hypochlorite-induced fibrosis was likely due to necrosis, but not programmed apoptosis; besides, overexpression of IL1β, CX3CL1 and TGFβ on the peritoneal mesothelium in current model was detected, similar to observations from peritoneal dialysis-induced peritoneal fibrosis in human patients and earlier reported mouse model. Moreover, our novel antemortem evaluation using laparoscopy provided instant feedback on the progression of organ fibrosis/adhesion which allows immediate adjustments on treatment protocols and strategies in alive individuals that can not and never be performed in other animal models.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypochlorite-induced porcine model of peritoneal fibrosis through the activation of IL1β-CX3CL1-TGFβ1 signal axis

Hsu

Chao

et al. 2020

Sci Rep

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“…In many culture systems, IL‐17A serves as an adjuvant to other cytokines such as TNFα rather than as a direct stimulator of endothelial or epithelial cells [1, 7]. In PD, upregulation of the Th17‐related cytokines IL‐6 [10] and IL‐1β [11, 12] is established. Together with IL‐17, they can form a self‐promoting loop.…”

Section: Introductionmentioning

confidence: 99%

Peritoneal dialysate‐range hypertonic glucose promotes T‐cell IL‐17 production that induces mesothelial inflammation

et al. 2020

Self Cite

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Peritoneal dialysis (PD) employs hypertonic glucose to remove excess water and uremic waste. Peritoneal membrane failure limits its long‐term use. T‐cell cytokines promote this decline. T‐cell differentiation is critically determined by the microenvironment. We here study how PD‐range hypertonic glucose regulates T‐cell polarization and IL‐17 production. In the human peritoneal cavity, CD3+ cell numbers increased in PD. Single cell RNA sequencing detected expression of T helper (Th) 17 signature genes RORC and IL23R. In vitro, PD‐range glucose stimulated spontaneous and amplified cytokine‐induced Th17 polarization. Osmotic controls l‐glucose and d‐mannose demonstrate that induction of IL‐17A is a substance‐independent, tonicity dose‐dependent process. PD‐range glucose upregulated glycolysis and increased the proportion of dysfunctional mitochondria. Blockade of reactive‐oxygen species (ROS) prevented IL‐17A induction in response to PD‐range glucose. Peritoneal mesothelium cultured with IL‐17A or IL17F produced pro‐inflammatory cytokines IL‐6, CCL2, and CX3CL1. In PD patients, peritoneal IL‐17A positively correlated with CX3CL1 concentrations. PD‐range glucose‐stimulated, but neither identically treated Il17a−/−Il17f−/− nor T cells cultured with the ROS scavenger N‐acetylcysteine enhanced mesothelial CX3CL1 expression. Our data delineate PD‐range hypertonic glucose as a novel inducer of Th17 polarization in a mitochondrial‐ROS‐dependent manner. Modulation of tonicity‐mediated effects of PD solutions may improve membrane survival.

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“…PMCs are the main composition of peritoneum, and convincing evidence has highlighted the deposition of ECM in PMCs plays a critical role in the PF. 17,18 Recently, some studies have reported that AngII is constitutively expressed by PMCs and initiates the production of TGF-β1, thus contributing to ECM deposition and the induction of PF. 19 ARBs may therefore be a powerful tool for preserving peritoneal function beyond blood pressure reduction.…”

Section: Discussionmentioning

confidence: 99%

Valsartan ameliorates high glucose-induced peritoneal ﬁbrosis by blocking mTORC1 signaling

Liu

Feng

Sun

et al. 2020

Exp Biol Med (Maywood)

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Our previous study demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) pathway is activated in peritoneal fibrosis under high glucose condition. This study aimed to investigate whether valsartan inhibits high glucose-induced peritoneal fibrosis via decreasing the activity of the mTORC1 pathway. We used high glucose peritoneal dialysis solution in a mouse peritoneal dialysis model to induce peritoneal fibrosis in vivo and high glucose in human peritoneal mesothelial cells (HPMCs) to stimulate extracellular matrix accumulation in vitro. After injections of peritoneal dialysis solution containing 4.25% glucose for four weeks, mice showed typical features of peritoneal fibrosis, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and higher expression of extracellular matrix proteins, such as α-smooth muscle actin (α-SMA) and collagen I. Oral gavage of valsartan significantly ameliorated these pathological changes at both week 6 and week 8. These effects of valsartan were closely correlated with a decrease in the activation of the mTORC1 signal, which was mediated by the downregulation of the protein expression of phosphorylated (p)-mTOR, p-eukaryotic initiation factor 4E-binding protein 1, and p-p70 S6 kinase 1. Further research showed that the protein expression of mTORC1 signal was positively correlated with the expression of both α-SMA and collagen I in the peritoneum. In vitro, high glucose increased the protein expression of α-SMA and collagen I in a dose-dependent manner, while valsartan significantly inhibited high glucose-induced extracellular matrix accumulation in HPMCs. The effect was also accompanied by a decrease in the activation of the mTORC1 signal. Furthermore, the mTOR agonist MHY1485 reversed the downregulation of extracellular matrix components in HPMCs, even in the presence of valsartan. We conclude that valsartan exerts a protective effect against high glucose-induced peritoneal fibrosis via suppressing the activity of the mTORC1 pathway. Impact statement Our study provided new insight into the mechanism underlying the preservation of the peritoneum by valsartan. The results demonstrated that the mice receiving chronic high glucose (HG) peritoneal dialysis solution infusion showed a typical feature of peritoneal fibrosis (PF), as well as higher expression of α-smooth muscle actin (α-SMA) and collagen I. In vitro, HG increased the protein expression of α-SMA and collagen I in a dose-dependent manner, while valsartan significantly ameliorated these pathological changes. Interestingly, there was a parallel decrease in the activity of mammalian target of rapamycin complex 1 (mTORC1) and the protein expression levels of α-SMA and collagen I upon treatment with valsartan in vivo and in vitro. Moreover, the mTOR agonist MHY1485 reversed the downregulation of α-SMA and collagen I in vitro, even in the presence of valsartan. Altogether, our findings reported for the first time that valsartan exerts a protective effect against HG-induced PF by inhibiting the activity of the mTORC1 pathway.

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CX3CL1–CX3CR1 interaction mediates macrophage-mesothelial cross talk and promotes peritoneal fibrosis

Cited by 49 publications

References 51 publications

Hypochlorite-induced porcine model of peritoneal fibrosis through the activation of IL1β-CX3CL1-TGFβ1 signal axis

Hypochlorite-induced porcine model of peritoneal fibrosis through the activation of IL1β-CX3CL1-TGFβ1 signal axis

Peritoneal dialysate‐range hypertonic glucose promotes T‐cell IL‐17 production that induces mesothelial inflammation

Valsartan ameliorates high glucose-induced peritoneal ﬁbrosis by blocking mTORC1 signaling

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