ORCID Profile
0000-0002-5687-0270
Current Organisations
Westmead Hospital
,
Westmead Institute for Medical Research
,
University of Sydney
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Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1038/S41374-019-0276-Z
Abstract: Transforming growth factor β (TGF-β) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-β to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. β-catenin is a common co-factor in most TGF-β signaling pathways. β-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Forkhead box O (Foxo) to promote cell survival under oxidative stress. Using a proximity ligation assay in human kidney biopsies, we found that β-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas β-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that β-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-β1-induced profibrotic protein expression using a CRISPR/cas9 knockout of Foxo1 or TCF1 in murine kidney tubular epithelial C1.1 cells. Co-administration of TGF-β with a small molecule inhibitor of β-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest β-catenin/Foxo as a therapeutic target in kidney fibrosis.
Publisher: Oxford University Press (OUP)
Date: 26-12-2019
DOI: 10.1093/NDT/GFY385
Abstract: Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103− DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.
Publisher: Wiley
Date: 07-2018
DOI: 10.1111/NEP.13166
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.KINT.2019.07.019
Abstract: Innate lymphoid cells are a recently recognized group of immune cells with critical roles in tissue homeostasis and inflammation. Regulatory innate lymphoid cells are a newly identified subset of innate lymphoid cells, which play a suppressive role in the innate immune response, favoring the resolution of intestinal inflammation. However, the expression and role of regulatory innate lymphoid cells in kidney has not been reported. Here, we show that regulatory innate lymphoid cells are present in both human and mouse kidney, express similar surface markers and form a similar proportion of total kidney innate lymphoid cells. Regulatory innate lymphoid cells from kidney were expanded in vitro with a combination of IL-2, IL-7 and transforming growth factor-β. These cells exhibited immunosuppressive effects on innate immune cells via secretion of IL-10 and transforming growth factor-β. Moreover, treatment with IL-2/IL-2 antibody complexes (IL-2C) promoted expansion of regulatory innate lymphoid cells in vivo, and prevent renal ischemia/reperfusion injury in Rag-/- mice that lack adaptive immune cells including Tregs. Depletion of regulatory innate lymphoid cells with anti-CD25 antibody abolished the beneficial effects of IL-2C in the Rag-/- mice. Adoptive transfer of ex vivo expanded regulatory innate lymphoid cells improved renal function and attenuated histologic damage when given before or after induction of ischemia/reperfusion injury in association with reduction of neutrophil infiltration and induction of reparative M2 macrophages in kidney. Thus, our study shows that regulatory innate lymphoid cells suppress innate renal inflammation and ischemia/reperfusion injury.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.KINT.2018.10.041
Abstract: Tissue macrophages are crucial players in homeostasis, inflammation, and immunity. They are characterized by heterogeneity and plasticity, due to which they display a continuum of phenotypes with M1/M2 presenting 2 extremes of this continuum. M2 macrophages are usually termed in the literature as anti-inflammatory and wound healing. Substantial progress has been made in elucidating the biology of M2 macrophages and their potential for clinical translation. In this review we discuss the current state of knowledge in M2 macrophage research with an emphasis on kidney disease. We explore their therapeutic potential and the challenges in using them as cellular therapies. Some new regulators that shape macrophage polarization and potential areas for future research are also examined.
Publisher: AMPCo
Date: 09-2015
DOI: 10.5694/MJA15.00241
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-01-2018
Abstract: The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33–treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo –expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of hiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo –expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33–ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2014
Publisher: Elsevier BV
Date: 06-2016
Publisher: Elsevier BV
Date: 04-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-03-2018
Abstract: Dialysis patients have an exceedingly high mortality rate. Biomarkers may be useful tools in risk stratification of this population. We evaluated the prognostic value of high‐sensitivity cardiac troponin T (hs‐ cTnT ) and CRP (C‐reactive protein) in predicting adverse outcomes in stable hemodialysis and peritoneal dialysis ( PD ) patients. Variability in hs‐ cTnT was also examined. A retrospective cohort study included 574 dialysis patients (hemodialysis 347, PD 227). Outcomes examined included mortality and major adverse cardiovascular events, with median follow‐up of 3.5 years. hs‐ cTnT was an independent predictor of both outcomes in hemodialysis and PD patients. Increased risk only became significant when hs‐ cTnT reached quintile 3 ( ng/L). Area under the receiver operating curve analysis showed that the addition of hs‐ cTnT to clinical parameters significantly improved its prognostic performance for mortality in PD patients ( P =0.002). CRP was an independent predictor of both outcomes in PD patients only. Only CRP in the highest quintile ( .8 mg/L) was associated with increased risk. hs‐ cTnT remained relatively stable for the whole follow‐up period for hemodialysis patients, whereas for PD patients, hs‐ cTnT increased by 23.63% in year 2 and 29.13% in year 3 compared with baseline ( P .001). hs‐ cTnT and CRP are useful tools in predicting mortality and major adverse cardiovascular events in hemodialysis and PD patients. Given that hs‐ cTnT levels increase over time in PD patients, interval monitoring may be valuable for risk assessment. In contrast, hs‐ cTnT in hemodialysis patients has little interval change and progress monitoring is not indicated.
No related grants have been discovered for Titi Chen.