Dataset Information

Absence of Nonclassical Monocytes in Hemolytic Patients: Free Hb and NO-Mediated Mechanism.

ABSTRACT: In a recent work, we have described the kinetics among the monocyte subsets in the peripheral blood of hemolytic patients including paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD). After engulfing Hb-activated platelets, classical monocytes (CD14+CD16-) significantly transformed into highly inflammatory (CD14+CD16hi) subsets in vitro. An estimated 40% of total circulating monocytes in PNH and 70% in SCD patients existed as CD14+CD16hi subsets. In this study, we show that the nonclassical (CD14dimCD16+) monocyte subsets are nearly absent in patients with PNH or SCD, compared to 10-12% cells in healthy individuals. In mechanism, we have described the unique role of both free Hb and nitric oxide (NO) in reducing number of nonclassical subsets more than classical monocytes. After engulfing Hb-activated platelets, the monocytes including nonclassical subsets acquired rapid cell death within 12?h in vitro. Further, the treatment to monocytes either with the secretome of Hb-activated platelets containing NO and free Hb or purified free Hb along with GSNO (a physiological NO donor) enhanced rapid cell death. Besides, our data from both PNH and SCD patients exhibited a direct correlation between intracellular NO and cell death marker 7AAD in monocytes from the peripheral blood. Our data together suggest that due to the immune surveillance nature, the nonclassical or patrolling monocytes are encountered frequently by Hb-activated platelets, free Hb, and NO in the circulation of hemolytic patients and are predisposed to die rapidly.

SUBMITTER: Singhal R

PROVIDER: S-EPMC6458887 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Absence of Nonclassical Monocytes in Hemolytic Patients: Free Hb and NO-Mediated Mechanism.

Singhal Rashi R Rathore Deepak K DK Bhakuni Teena T Seth Tulika T Guchhait Prasenjit P

Journal of immunology research 20190327

In a recent work, we have described the kinetics among the monocyte subsets in the peripheral blood of hemolytic patients including paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD). After engulfing Hb-activated platelets, classical monocytes (CD14+CD16-) significantly transformed into highly inflammatory (CD14+CD16hi) subsets in vitro. An estimated 40% of total circulating monocytes in PNH and 70% in SCD patients existed a ...[more]

PMID: 31032371

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Project description:BackgroundEmerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system.MethodsTo address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau (n = 8), and healthy non-carrier controls (n = 8). Primary findings from our scRNA-seq analyses were confirmed and extended via flow cytometry, droplet digital (dd)PCR, and secondary analyses of publicly available transcriptomics datasets.ResultsAnalysis of ~ 181,000 individual PBMC transcriptomes demonstrated striking differential expression in monocytes and natural killer (NK) cells in MAPT pathogenic variant carriers. In particular, we observed a marked reduction in the expression of CX3CR1-the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models-in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia but with unclear function in peripheral monocytes. We confirmed the reduction in nonclassical monocytes by flow cytometry and the differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using ddPCR.ConclusionsOur results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

Dataset Information

Absence of Nonclassical Monocytes in Hemolytic Patients: Free Hb and NO-Mediated Mechanism.

Publications

Absence of Nonclassical Monocytes in Hemolytic Patients: Free Hb and NO-Mediated Mechanism.

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