Macrophages Expressing Heme Oxygenase-1 Improve Renal Function in Ischemia/Reperfusion Injury

Ferenbach, David A.; Ramdas, Vasudev; Spencer, Nishrin; Marson, Lorna; Anegón, Ignacio; Hughes, Jeremy; Kluth, David

doi:10.1038/mt.2010.100

Cited by 81 publications

(85 citation statements)

References 51 publications

(63 reference statements)

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“…20 In this study, we measured the levels of extracellular NO and TNF-α as they are relevant effector molecules that contribute to glomerular injury in numerous experimental models of glomerulonephritis. [30][31][32] Consistent with Zhou's report, the high levels of NO and TNF-α released by the LPS-stimulated MCs were effectively attenuated by co-incubation with TP for 24 h ( Figure 5). TRX-20 has a high affinity for MCs, 16 and this specificity was exploited in this study to develop renal-targeted therapy of TP.…”

Section: Anti-inflammatory Activity Of Trx-tp-lp and Peg-trx-tp-lpsupporting

confidence: 76%

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes

Yuan

Jia

Lim

et al. 2017

IJN

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Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios – 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) – of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC 50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG 5000 (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN.

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Section: Anti-inflammatory Activity Of Trx-tp-lp and Peg-trx-tp-lpsupporting

confidence: 76%

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes

Yuan

Jia

Lim

et al. 2017

IJN

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“…As HO-1 is known to have potent antiapoptotic effects, the enhanced rate of apoptosis in Btk-deficient mice may be due to a decreased upregulation of HO- effects in experimental models of various inflammatory disorders such as arthritis, encephalomyelitis, and hepatitis (2,17). Moreover, targeted overexpression of HO-1 in macrophages has been shown to protect against ischemia-reperfusion injury in experimental mouse models of liver and kidney transplantation (62,63).…”

Section: Significance Of Btk-dependent Ho-1 Regulation In Innate and mentioning

confidence: 99%

Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages

Vijayan

Baumgart-Vogt

Naidu

et al. 2011

The Journal of Immunology

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Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and provides cytoprotection against oxidative stress by its products carbon monoxide and biliverdin. More recently, HO-1 has also been shown to exert immunomodulatory functions via cell type-specific anti-inflammatory effects in myeloid/macrophage cells. In the current study, it is demonstrated that Bruton's tyrosine kinase (Btk), the gene of which is mutated in the human immunodeficiency X-linked agammaglobulinemia, is involved in the upregulation of HO-1 gene expression via TLR signaling in macrophages. The specific Btk inhibitor LFM-A13 blocked HO-1 induction by the classical TLR4 ligand LPS in cell cultures of RAW264.7 monocytic cells and primary mouse alveolar macrophages. Moreover, upregulation of HO-1 gene expression was abrogated in LPS-stimulated alveolar macrophages from Btk−/− mice. Transfection studies with luciferase reporter gene constructs demonstrated that LPS-dependent induction of HO-1 promoter activity was attenuated by pharmacological Btk inhibition and by an overexpressed dominant-negative mutant of Btk. This induction was mediated by the transcription factor Nrf2, which is a master regulator of the antioxidant cellular defense. Accordingly, nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. The generation of reactive oxygen species, but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression was also observed upon macrophage stimulation with ligands of TLR2, TLR6, TLR7, and TLR9, suggesting that Btk is required for HO-1 gene activation by major TLR pathways.

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“…5 A and B). To confirm the active secretion of MMPs and determine if this effect was a general effect of phagocytosis on macrophages independent of the type of debris, we used the well-described model of phagocytosis of apoptotic thymocytes (46). Culture supernatants from BMDMs fed with apoptotic thymocytes for 12 h showed a robust increase in active MMP-9 and MMP-12 secretion detected by gelatin zymography and Western blotting, respectively ( Fig.…”

Section: Macrophage Phagocytosis In Vitro Induces a Matrix-degradingmentioning

confidence: 99%

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Ramachandran

Pellicoro

Vernon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

792

907

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Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl 4 -induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B hi F4/80 int Ly-6C lo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter-diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C hi monocytes, a common origin with profibrotic Ly-6C hi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C lo subset, compared with Ly-6C hi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.

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Macrophages Expressing Heme Oxygenase-1 Improve Renal Function in Ischemia/Reperfusion Injury

Cited by 81 publications

References 51 publications

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes

Bruton’s Tyrosine Kinase Is Required for TLR-Dependent Heme Oxygenase-1 Gene Activation via Nrf2 in Macrophages

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

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