FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2034625189> ?p ?o ?g. }

• W2034625189 endingPage "2069" @default.
• W2034625189 startingPage "2067" @default.
• W2034625189 abstract "Heme oxygenase 1 (HO-1) is a readily inducible enzyme that converts highly reactive free heme molecules into carbon monoxide, iron, and biliverdin. Through this action, HO-1 influences reactive intermediate production, modulates the immune system, and affects cell survival in multiple pathogenic situations. In humans, HO-1 deficiency is associated with severe hemolysis, dysregulated inflammation, renal abnormalities, and early death.1,2 After stress or pharmacologic manipulation, HO-1 is upregulated in numerous tissues including the renal vasculature, tubular epithelial cells, and renal interstitial cells expressing the resident macrophage/dendritic cell (DC) marker CD68.3,4 Novel techniques and mouse models have recently begun to reveal how HO-1 in different cell types influences disease. For example, use of a tissue-specific knockout strategy demonstrated that HO-1 expression in myeloid cells (including neutrophils, monocytes/macrophages, and DCs) is critical for limiting pathology in a mouse model of multiple sclerosis, because myeloid-specific HO-1 deficiency resulted in chronic activation of DCs and enhanced accumulation of proinflammatory T cells in the spinal cord.5 Alternatively, HO-1 deletion exclusively from hepatocytes or myeloid cells improves insulin sensitivity and reduces inflammation and metabolic syndrome induced by a high-fat diet in mice, whereas specific HO-1 deletion from muscle, adipocytes, or pancreatic β cells had no effect.6 These findings demonstrate that HO-1 can have disparate functions depending on the cell type and nature of the pathology being studied. A protective role for HO-1 in AKI models including kidney ischemia reperfusion injury (IRI), cisplatin nephrotoxicity, and others has been recognized for many years (see Nath7 and references therein). HO-1 expression is induced quickly in the kidney during injury and HO-1 activity serves to limit renal injury and dysfunction. This is dramatically illustrated by the finding that HO-1–deficient mice exhibit severe renal dysfunction at 1 day, and >50% mortality at 2–5 days after 15 minutes8 or 10 minutes9 of renal ischemia. This length of ischemia does not result in significant renal injury or dysfunction or any mortality in wild-type control mice.8,9 The clinical relevance of HO-1 in AKI was recently bolstered by several important studies, including the demonstration that HO-1 levels in plasma and urine reflect intrarenal HO-1 activity and increase specifically in human AKI.10 Furthermore, transgenic expression of human HO-1 in HO-1–deficient mice reverses the heightened sensitivity to rhabdomyolysis and cisplatin nephrotoxicity.11 The proinflammatory immune response observed in AKI models is well known to enhance the direct nephrotoxic or ischemic damage to renal cells,12,13 and HO-1 has direct effects on numerous types of immune cells.14 Of note, infusion of macrophages that overexpress HO-1 after IRI ameliorates kidney dysfunction in mice,15 and global knockout of HO-1 promotes renal inflammation in AKI models.8,16 In this issue of JASN, Hull et al.9 significantly advance our understanding of the role of HO-1 that is expressed in myeloid immune cells in the kidney IRI model. Using flow cytometry to carefully examine the effect of global HO-1 deficiency on renal inflammation during reperfusion, a marked increase in the number of neutrophils and monocytes/macrophages infiltrating the kidney was observed at 1 day of reperfusion in HO-1 knockout (KO) mice versus controls.9 This finding is in line with the renal-protective and anti-inflammatory role attributed to HO-1 in IRI.7,15 Strikingly, at the same time, there was a dramatic reduction in the number and proportion of renal DCs after ischemia in the HO-1 KO mice.9 DCs are known to traffick from the postischemic kidney to the renal draining lymph node where they present antigens to T cells,17 and enhanced trafficking could explain the reduction in renal DCs observed in HO-1–deficient mice. DCs are key modulators of different types of AKI, which can either protect the kidney from injury,18 or promote renal injury,19 depending on the type of injury and the type of activation signals received by the DCs, so enhanced understanding of DC activation and trafficking in AKI may lead to new therapeutic approaches. To elegantly address the question of whether HO-1 influences the emigration of renal DCs to lymphatic organs, syngeneic kidney transplants were performed implanting HO-1+/+ or HO-1−/− kidneys from mice that ubiquitously express green fluorescent protein (GFP) into GFP-negative recipients.9 In these experiments, the warm ischemic time for each graft was tightly controlled and limited to 25 minutes. Using immunofluorescence microscopy and flow cytometry, the number of HO-1+/+ and HO-1−/− DCs was quantified in the spleen, renal draining lymph node, and mesenteric lymph node.9 This experiment clearly demonstrated that HO-1−/− MHC-II+ DCs traffick in greater numbers to each of these extrarenal lymphoid organs as early as 1 day after transplantation. To complement the transplantation study, mice lacking HO-1 expression solely in myeloid immune cells and control mice were subjected to 25 minutes of bilateral renal IRI. After 3 days of reperfusion, analysis of renal immune cells by flow cytometry demonstrated that lack of HO-1 expression in myeloid cells alone was sufficient to cause the reduction in renal DCs and increase in infiltration of monocytes/macrophages; however, myeloid-specific deletion of HO-1 did not result in the enhanced renal neutrophil accumulation observed in the global HO-1 KO mice after IRI.9 Thus, expression of HO-1 by renal DCs appears to promote their retention in the postischemic kidney and HO-1 expression in monocytes/macrophages impairs their ability to accumulate in the kidney after ischemia. To address the biologic significance of the altered immune cell trafficking in the myeloid-specific HO-1–deficient mice, renal function, histology, and markers of fibrosis were monitored for 7 days after ischemia. No difference in initial renal injury or dysfunction was noted between controls and myeloid HO-1 KO mice. However, at 7 days after IRI, enhanced renal function was observed in control mice and more fibronectin and collagen expression was detected in the myeloid HO-1 KO mice.9 The reasons for impaired renal recovery and increased expression of markers of fibrosis have not been determined, but could be due to several possibilities. First, HO-1 is preferentially expressed in M2 macrophages and associated with their function,20 and the in situ switch of proinflammatory M1-type macrophages to M2 in the kidney after IRI is required for appropriate renal recovery.21,22 Second, retention of HO-1–expressing DCs in the kidney may promote the function of kidney-infiltrating regulatory T cells that positively influence the recovery of renal function and reduce fibrosis after IRI,23,24 because expression of HO-1 in DCs is required for optimal regulatory T cell function.25 Another possibility is that the increased trafficking of DCs from the ischemic kidney to secondary lymphoid organs may induce a more robust adaptive immune response to the injured kidney, limiting the ability of the kidney to recover. None of these possibilities are mutually exclusive and there are numerous other possibilities that may explain why the lack of HO-1 in myeloid cells inhibits recovery from AKI. Another interesting finding presented in the article by Hull et al.9 is that although global HO-1 deficiency caused enhanced neutrophil homing to the kidney after IRI, myeloid-restricted HO-1 deficiency did not cause increased neutrophil accumulation.9 This is in contrast with the parallel effects of either global or myeloid-specific deletion of HO-1 on monocyte/macrophage infiltration to and DC emigration from the injured kidney, illustrating the complexity and specificity of the effects of HO-1 expressed in different cell types in kidney IRI. Given the human relevance of HO-1 in AKI and the growing understanding of the myeloid cells in renal health and disease,26 these studies by Hull et al.9 provide the foundation for a new area of AKI research. Disclosures None. G.R.K. is supported by grants from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (K01-DK088967 and R03-DK099489). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health." @default.
• W2034625189 created "2016-06-24" @default.
• W2034625189 creator A5072442015 @default.
• W2034625189 date "2015-09-01" @default.
• W2034625189 modified "2023-10-13" @default.
• W2034625189 title "Myeloid Cell HO-ming in AKI" @default.
• W2034625189 cites W1600560134 @default.
• W2034625189 cites W1964135599 @default.
• W2034625189 cites W1966033287 @default.
• W2034625189 cites W1971799714 @default.
• W2034625189 cites W1982260752 @default.
• W2034625189 cites W1985491668 @default.
• W2034625189 cites W2005355453 @default.
• W2034625189 cites W2009521826 @default.
• W2034625189 cites W2010708756 @default.
• W2034625189 cites W2016318035 @default.
• W2034625189 cites W2024314608 @default.
• W2034625189 cites W2047124888 @default.
• W2034625189 cites W2068825117 @default.
• W2034625189 cites W2071430851 @default.
• W2034625189 cites W2075372904 @default.
• W2034625189 cites W2077940334 @default.
• W2034625189 cites W2083383675 @default.
• W2034625189 cites W2092741113 @default.
• W2034625189 cites W2095337395 @default.
• W2034625189 cites W2104760558 @default.
• W2034625189 cites W2110720586 @default.
• W2034625189 cites W2120505405 @default.
• W2034625189 cites W2124267728 @default.
• W2034625189 cites W2136049487 @default.
• W2034625189 cites W2149912188 @default.
• W2034625189 cites W2168784022 @default.
• W2034625189 cites W2318436667 @default.
• W2034625189 doi "https://doi.org/10.1681/asn.2015010072" @default.
• W2034625189 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4552127" @default.
• W2034625189 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25677391" @default.
• W2034625189 hasPublicationYear "2015" @default.
• W2034625189 type Work @default.
• W2034625189 sameAs 2034625189 @default.
• W2034625189 citedByCount "1" @default.
• W2034625189 countsByYear W20346251892016 @default.
• W2034625189 crossrefType "journal-article" @default.
• W2034625189 hasAuthorship W2034625189A5072442015 @default.
• W2034625189 hasBestOaLocation W20346251891 @default.
• W2034625189 hasConcept C177713679 @default.
• W2034625189 hasConcept C203014093 @default.
• W2034625189 hasConcept C2779282312 @default.
• W2034625189 hasConcept C71924100 @default.
• W2034625189 hasConceptScore W2034625189C177713679 @default.
• W2034625189 hasConceptScore W2034625189C203014093 @default.
• W2034625189 hasConceptScore W2034625189C2779282312 @default.
• W2034625189 hasConceptScore W2034625189C71924100 @default.
• W2034625189 hasIssue "9" @default.
• W2034625189 hasLocation W20346251891 @default.
• W2034625189 hasLocation W20346251892 @default.
• W2034625189 hasLocation W20346251893 @default.
• W2034625189 hasLocation W20346251894 @default.
• W2034625189 hasOpenAccess W2034625189 @default.
• W2034625189 hasPrimaryLocation W20346251891 @default.
• W2034625189 hasRelatedWork W1506200166 @default.
• W2034625189 hasRelatedWork W1995515455 @default.
• W2034625189 hasRelatedWork W2048182022 @default.
• W2034625189 hasRelatedWork W2080531066 @default.
• W2034625189 hasRelatedWork W2604872355 @default.
• W2034625189 hasRelatedWork W2748952813 @default.
• W2034625189 hasRelatedWork W2899084033 @default.
• W2034625189 hasRelatedWork W3031052312 @default.
• W2034625189 hasRelatedWork W3032375762 @default.
• W2034625189 hasRelatedWork W3108674512 @default.
• W2034625189 hasVolume "26" @default.
• W2034625189 isParatext "false" @default.
• W2034625189 isRetracted "false" @default.
• W2034625189 magId "2034625189" @default.
• W2034625189 workType "article" @default.