Immune-Regulatory Molecule CD69 Controls Peritoneal Fibrosis.

Patients with ESRD undergoing peritoneal dialysis develop progressive peritoneal fibrosis, which may lead to technique failure. Recent data point to Th17-mediated inflammation as a key contributor in peritoneal damage. The leukocyte antigen CD69 modulates the setting and progression of autoimmune and inflammatory diseases by controlling the balance between Th17 and regulatory T cells (Tregs). However, the relevance of CD69 in tissue fibrosis remains largely unknown. Thus, we explored the role of CD69 in fibroproliferative responses using a mouse model of peritoneal fibrosis induced by dialysis fluid exposure under either normal or uremic status. We found that cd69-/- mice compared with wild-type (WT) mice showed enhanced fibrosis, mesothelial to mesenchymal transition, IL-17 production, and Th17 cell infiltration in response to dialysis fluid treatment. Uremia contributed partially to peritoneal inflammatory and fibrotic responses. Additionally, antibody-mediated CD69 blockade in WT mice mimicked the fibrotic response of cd69-/- mice. Finally, IL-17 blockade in cd69-/- mice decreased peritoneal fibrosis to the WT levels, and mixed bone marrow from cd69-/- and Rag2-/-γc-/- mice transplanted into WT mice reproduced the severity of the response to dialysis fluid observed in cd69-/- mice, showing that CD69 exerts its regulatory function within the lymphocyte compartment. Overall, our results indicate that CD69 controls tissue fibrosis by regulating Th17-mediated inflammation.

The dipeptide alanyl-glutamine ameliorates peritoneal fibrosis and attenuates IL-17 dependent pathways during peritoneal dialysis.

Peritoneal dialysis (PD) can result in chronic inflammation and progressive peritoneal membrane damage. Alanyl-Glutamine (Ala-Gln), a dipeptide with immunomodulatory effects, improved resistance of mesothelial cells to PD fluids. Recently, interleukin-17 (IL-17) was found to be associated with PD-induced peritoneal damage. Here we studied the capacity of intraperitoneal Ala-Gln administration to protect against peritoneal damage by modulating IL-17 expression in uremic rat and mouse PD exposure models. Supplementation of PD fluid with Ala-Gln resulted in reduced peritoneal thickness, αSMA expression and angiogenesis. Addition of Ala-Gln also attenuated the IL-17 pathway expression induced by PD, reflected by substantial reduction or normalization of peritoneal levels of IL-17, transforming growth factor ß, IL-6, and the transcription factor retinoic acid receptor-related orphan receptor gamma T. Moreover, increased levels of IL-17 were associated with PD-induced peritoneal thickening. Conversely, Ala-Gln treatment prevented peritoneal extracellular matrix deposition, an effect seen with IL-17 blockade. Thus, intraperitoneal administration of Ala-Gln, a stable dipeptide commonly used in parenteral nutrition, ameliorates PD-induced peritoneal damage in animal models, in part by modulating IL-17 expression. Hence, Ala-Gln supplementation of dialysate may be a potential strategy to ameliorate peritoneal deterioration during PD.

Corrigendum to "T Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage".

[This corrects the article DOI: 10.1155/2015/416480.].

Nebivolol, a ß1-adrenergic blocker, protects from peritoneal membrane damage induced during peritoneal dialysis.

UNLABELLED: Peritoneal dialysis (PD) is a form of renal replacement treatment, which employs the peritoneal membrane (PM) to eliminate toxins that cannot be removed by the kidney. The procedure itself, however, contributes to the loss of the PM ultrafiltration capacity (UFC), leading consequently to the technique malfunction. ß-blockers have been considered deleterious for PM due to their association with loss of UFC and induction of fibrosis. Herein we analyzed the effects of Nebivolol, a new generation of ß1-blocker, on PM alterations induced by PD fluids (PDF).In vitro: We found that mesothelial cells (MCs) express ß1-adrenergic receptor. MCs were treated with TGF-ß to induce mesothelial-to-mesenchymal transition (MMT) and co-treated with Nebivolol. Nebivolol reversed the TGF-ß effects, decreasing extracellular matrix synthesis, and improved the fibrinolytic capacity, decreasing plasminogen activator inhibitor-1 (PAI-1) and increasing tissue-type plasminogen activator (tPA) supernatant levels. Moreover, Nebivolol partially inhibited MMT and decreased vascular endothelial growth factor (VEGF) and IL-6 levels in supernatants.In vivo: Twenty-one C57BL/6 mice were divided into 3 groups. Control group carried a catheter without PDF infusion. Study group received intraperitoneally PDF and oral Nebivolol during 30 days. PDF group received PDF alone. Nebivolol maintained the UFC and reduced PM thickness, MMT and angiogenesis promoted by PDF. It also improved the fibrinolytic capacity in PD effluents decreasing PAI-1 and IL-8 and increased tPA levels. CONCLUSION: Nebivolol protects PM from PDF-induced damage, promoting anti-fibrotic, anti-angiogenic, anti-inflammatory and pro-fibrinolytic effects.

T Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage.

Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD) treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT) are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Treg-axis in fibrotic diseases. Moreover, it compares current evidences described in PD animal experimental models, indicating a loss of Th17/Treg balance (Th17 predominance) leading to peritoneal damage during PD. In addition, considering the new clinical and animal experimental data, new therapeutic strategies to reduce the Th17 response and increase the regulatory T response are proposed. Thus, future goals should be to develop new clinical biomarkers to reverse this immune misbalance and reduce peritoneal fibrosis in PD.

Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis.

The contribution of chronic skin inflammation to the development of squamous cell carcinoma (SCC) is poorly understood. While the mitogen-activated protein kinase p38α regulates inflammatory responses and tumour development, little is known about the role of p38γ and p38δ in these processes. Here we show that combined p38γ and p38δ (p38γ/δ) deletion blocked skin tumour development in a chemically induced carcinogenesis model. p38γ/δ deletion reduced TPA-induced epidermal hyperproliferation and inflammation; it inhibited expression of proinflammatory cytokines and chemokines in keratinocytes in vitro and in whole skin in vivo, resulting in decreased neutrophil recruitment to skin. Our data indicate that p38γ/δ in keratinocytes promote carcinogenesis by enabling formation of a proinflammatory microenvironment that fosters epidermal hyperproliferation and tumourigenesis. These findings provide genetic evidence that p38γ and p38δ have essential roles in skin tumour development, and suggest that targeting inflammation through p38γ/δ offers a therapeutic strategy for SCC treatment and prevention.

Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT.

Preservation of peritoneal membrane (PM) is essential for long-term survival in peritoneal dialysis (PD). Continuous presence of PD fluids (PDF) in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT) and endothelial-to-mesenchymal transition (Endo-MT) seem to play a central role in this pathogenesis. We speculated that Rapamycin, a potent immunosuppressor, could be beneficial by regulating blood and lymphatic vessels proliferation. We demonstrate that mice undergoing a combined PD and Rapamycin treatment (PDF + Rapa group) presented a reduced PM thickness and lower number of submesothelial blood and lymphatic vessels, as well as decreased MMT and Endo-MT, comparing with their counterparts exposed to PD alone (PDF group). Peritoneal water transport in the PDF + Rapa group remained at control level, whereas PD effluent levels of VEGF, TGF-ß, and TNF-α were lower than in the PDF group. Moreover, the treatment of mesothelial cells with Rapamycin in vitro significantly decreased VEGF synthesis and selectively inhibited the VEGF-C and VEGF-D release when compared with control cells. Thus, Rapamycin has a protective effect on PM in PD through an antifibrotic and antiproliferative effect on blood and lymphatic vessels. Moreover, it inhibits Endo-MT and, at least partially, MMT.

Paricalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production.

Fibrosis is a significant health problem associated with a chronic inflammatory reaction. The precise mechanisms involved in the fibrotic process are still poorly understood. However, given that inflammation is a major causative factor, immunomodulation is a possible therapeutic approach to reduce fibrosis. The vitamin D receptor (VDR) that is present in all hematopoietic cells has been associated with immunomodulation. We investigated whether the intraperitoneal administration of paricalcitol, a specific activator of the VDR, modulates peritoneal dialysis fluid (PDF)-induced peritoneal fibrosis. We characterized the inflammatory process in the peritoneal cavity of mice treated or not treated with paricalcitol and analyzed the ensuing fibrosis. The treatment reduced peritoneal IL-17 levels, which strongly correlated with a significantly lower peritoneal fibrotic response. In vitro studies demonstrate that both CD4+ and CD8+ regulatory T cells appear to impact the regulation of IL-17. Paricalcitol treatment resulted in a significantly increased frequency of CD8+ T cells showing a regulatory phenotype. The frequency of CD4+ Tregs tends to be increased, but it did not achieve statistical significance. However, paricalcitol treatment increased the number of CD4+ and CD8+ Treg cells in vivo. In conclusion, the activation of immunological regulatory mechanisms by VDR signaling could prevent or reduce fibrosis, as shown in peritoneal fibrosis induced by PDF exposure in mice.