The human reticulocyte transcriptome

Goh, Sung‐Ho; Josleyn, Matthew; Lee, Y. Terry; Danner, Robert L.; Gherman, Robert B.; Cam, Maggie; Miller, Jeffery L.

doi:10.1152/physiolgenomics.00247.2006

Cited by 89 publications

(87 citation statements)

References 19 publications

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“…CD45 was not detectable in either SS or AA RBC lysates, whereas NOX1 and NOX2 were clearly present, indicating that WBC contamination of our RBC preps was minimal. Of note, mRNA for a variety of the subunits of the different NADPH oxidase subtypes have been detected in human adult and cord blood reticulocytes (supplemental Figure 1; data retrieved from www.ncbi.nlm.nih.gov/gds/, records 2655 and 2656), 32 supporting our findings that the NOX isoforms present in RBC are endogenous.…”

Section: Both Normal and Sickle Rbc Contain Several Nadph Oxidase Isosupporting

confidence: 82%

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

George

Pushkaran

Konstantinidis

et al. 2013

Blood

172

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• Sickle RBC ROS production is mediated in part by NADPH oxidase activity.• Sickle RBC ROS production can be induced by plasma signaling molecules.Chronic inflammation has emerged as an important pathogenic mechanism in sickle cell disease (SCD). One component of this inflammatory response is oxidant stress mediated by reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells (RBC). Sickle RBC ROS generation has been attributed to sickle hemoglobin auto-oxidation and Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane. In this study, we demonstrate that a significant part of ROS production in sickle cells is mediated enzymatically by NADPH oxidase, which is regulated by protein kinase C, Rac GTPase, and intracellular Ca 21 signaling within the sickle RBC. Moreover, plasma from patients with SCD and isolated cytokines, such as transforming growth factor b1 and endothelin-1, enhance RBC NADPH oxidase activity and increase ROS generation. ROS-mediated damage to RBC membrane components is known to contribute to erythrocyte rigidity and fragility in SCD. Erythrocyte ROS generation, hemolysis, vaso-occlusion, and the inflammatory response to tissue damage may therefore act in a positive-feedback loop to drive the pathophysiology of sickle cell disease. These findings suggest a novel pathogenic mechanism in SCD and may offer new therapeutic targets to counteract inflammation and RBC rigidity and fragility in SCD. (Blood. 2013;121(11):2099-2107 IntroductionVaso-occlusion and hemolysis from the rigid and concurrently fragile red blood cells (RBC) in patients with sickle cell disease (SCD) cause a variety of acute and chronic manifestations ranging from frequent and severe painful crises to stroke and chronic organ failure. Chronic inflammation has emerged as an important pathogenic mechanism in SCD, and oxidative stress is increasingly recognized as a component of this chronic inflammatory state, inducing damage to a variety of subcellular and tissue structures. 1,2Patients with SCD have decreased plasma levels of glutathione, vitamin C, and vitamin E, presumably due to consumption by increased oxidant production. [3][4][5] RBC and other cell types show evidence of lipid peroxidation and oxidative damage to structural proteins.6-8 Additionally, plasma from SCD patients has elevated levels of advanced glycation end products 9,10 and products of lipid peroxidation (F-2 isoprostanes, malonaldehyde, and 4-hydroxynonenal), [11][12][13] all of which are markers of oxidative stress. There are several postulated mechanisms for the increased oxidative stress in patients with SCD. Sickle (SS) RBC reactive oxygen species (ROS) generation has been attributed to sickle hemoglobin auto-oxidation and iron-mediated Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane.14 Plasma hemoglobin and free heme resulting from chronic hemolysis generate superoxide radicals via the same nonenzymatic mechanisms. 15 In...

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Section: Both Normal and Sickle Rbc Contain Several Nadph Oxidase Isosupporting

confidence: 82%

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

George

Pushkaran

Konstantinidis

et al. 2013

Blood

172

View full text Add to dashboard Cite

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“…All these genes were known to be expressed in the mouse bone marrow and human early erythrocytes expressing the transferring receptor. 15 In addition, disruption of several of these genes (Ank1, Klf1, Tfrc and Nfe2) has been shown to cause severe anemia. [16][17][18][19][20][21] Another group of genes involved in type 1 IFN signaling (Ifitm1, Irf7, Oas1, Oas2, Oasl, Isg15 and Usp18) were upregulated in the B6.MOLF-Ity/Ity2.RecD strain.…”

Section: Resultsmentioning

confidence: 99%

Refinement of the genetics of the host response to Salmonella infection in MOLF/Ei: regulation of type 1 IFN and TRP3 pathways by Ity2

et al. 2011

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Typhoid fever, which is caused by Salmonella typhi and paratyphi, is a severe systemic disease that remains a major public health issue in several areas of the world. We can model the human disease using mice infected with a related bacterium, Salmonella typhimurium. This model recapitulates several clinical aspects of the human disease and allows for the study of the host response to Salmonella typhimurium infection in vivo. Previous work in our laboratory has identified three Immunity to typhimurium loci (Ity, Ity2 and Ity3) in the wild-derived MOLF/Ei mice, influencing survival after infection with Salmonella typhimurium. The MOLF/Ei alleles at Ity and Ity2 are protective, while the MOLF/Ei allele at Ity3 confers susceptibility. In this paper, we have generated a novel cross combination between the highly susceptible strain, MOLF/Ei, and the resistant strain, 129S6, to better define the genetic architecture of susceptibility to infection in MOLF/Ei. Using this cross, we have replicated the locus on chr 11 (Ity2) and identified a novel locus on chr 13 (Ity13). Using microarrays and transcriptional profiling, we examined the response of uninfected and infected Ity2 congenic mice. These analyses demonstrate a role for both type-1-interferon (IFN) and TRP53 signaling in the pathogenesis of Salmonella infection.

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“…This is also suggested by the similar reduction of LMO2 mRNA obtained either by siLMO2 and by miR-223. Interestingly, miR-223 17 and LMO2 37,38 (A. Zeuner, unpublished data, 2006) expression are inversely related in erythroid cultures derived from adult blood suggesting that LMO2 regulation may be a relevant mechanism involved also in the control of adult erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%