Persistent imbalance, anti-apoptotic, and anti-inflammatory signature of circulating C-C chemokines and cytokines in patients with paroxysmal nocturnal hemoglobinuria. (February 2022)

• Record Type: Journal Article
• Authors: Szlendak, Urszula; Krzymieniewska, Beata; Mendek-Czajkowska, Ewa; Rogatko-Koroś, Marta; Witkowska, Agnieszka; Włodarska, Joanna; Drozd-Sokołowska, Joanna; Spychalska, Justyna; Budziszewska, Bożena; Patkowska, Elżbieta; Woźniak, Jolanta; Krzywdzińska, Agnieszka; Jurek, Sławomir; Juszczyński, Przemysław; Jaworska, Małgorzata; Rosłon, Magdalena; Gruber-Bzura, Beata; Wasilewski, Robert; Baran, Beata; Windyga, Jerzy; Nowak, Jacek
• Is Part Of: Cytokine. Volume 150(2022)
• Publication Date: 2022-02
• Subjects: CCL3 or MIP-1α macrophage inflammatory protein-1 alpha -- CCL4 or MIP-1β macrophage inflammatory protein-1 beta -- CCL2 or MCP-1 monocyte chemoattractant protein-1 -- CCL5 or RANTES regulated upon activation normal T cell expressed and secreted protein -- PDGF platelet-derived growth factor -- IL1ra IL1 receptor antagonist -- Basic FGF or FGF-2 basic fibroblast growth factor -- CXCL10 or IP-10 interferon-γ-inducible protein -- IFN-γ interferon-γ -- TNF-α tumor necrosis factor -- VEGF vascular endothelial growth factor -- PI(3, 4, 5)P3 phosphatidylinositol (3, 4, 5)-trisphosphate -- FLAER Fluorescein-labeled proaerolysin -- GPR75 G protein-coupled receptor 75 -- HPCs hematopoietic cells -- LyNo lymph node cells -- PDGFR-β platelet-derived growth factor receptor beta -- Spl spleen cells -- Strom bone marrow stromal cells -- GPI glycosylphosphatidylinositol -- PI(4)P phosphatidylinositol 4-phosphate -- PI(4, 5)P2 phosphatidylinositol 4, 5-bisphosphate -- PI3K phosphatidylinositol 3-kinase -- PI4K phosphatidylinositol 4-kinase -- PI(4)P5Kα Phosphatidylinositol 4-phosphate 5-kinase; Paroxysmal nocturnal hemoglobinuria -- Cytokines -- Chemokines -- Apoptosis -- Phosphatidylinositol (3, 4, 5)-trisphosphate -- Hematopoietic stem/progenitor cells; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2021.155780
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: Cytokine biosignature for PNH exist in patients' plasma. CCL3 strongly associate with anti-apoptotic phenotype of stem cells with PNH defect. CCL5, CCL4, PDGF-BB and IL9 negatively associate with anti-apoptotic PNH CD34+. CD34+ cells in PNH express anti-apoptotic phenotype and high PI(3, 4, 5)P3 content. A skewed cytokine equilibrium does not confirm cell-mediated immune attack in PNH. Abstract: Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant disease in which hematopoietic cell apoptosis may play an important pathophysiological role. Previous studies of the content of phosphatidylinositol (3, 4, 5)-trisphosphate (PI(3, 4, 5)P3) indicated the possibility of remote transmission of anti-apoptotic signals between pathological and normal hematopoietic progenitors. Methods: The study determined the plasma levels of beta chemokines and cytokines in N = 19 patients with PNH and 31 healthy controls. The research material was peripheral blood plasma (EDTA) stored at −80 °C until the test. Beta chemokine and cytokine concentrations were tested in duplicate with Bio-Plex Pro Human Cytokine Assay (Bio-Rad, Hercules, CA, USA) using a Luminex 200 flow cytometer and xPONENT software (Luminex Corporation, Austin, TX, USA). In peripheral blood CD34+ cells we tested the proportions of PI(3, 4, 5)P3+ and Annexin binding apoptotic phenotype using FC and phosflow. Results: Compared to the control group, the PNH group showed a significant increase in the plasma concentration of some beta chemokines and cytokines, including MIP-1alpha/CCL3, eotaxin/CCL11, MCP1/CCL2, IL4 and G-CSF. In the group of PNH patients, a significant decrease in the concentration of some cytokines was also observed: RANTES/CCL5, MIP-1beta/CCL4, PDGF-BB and IL9. At the same time, the plasma concentrations of the chemokine IP-10/CXCL10 and the cytokines IFN-gamma, TNF, IL6 and IL10 showed no significant deviations from the values for the control group. Anti-apoptotic phenotype and phosphatidylinositol (3, 4, 5)-trisphosphate content in PNH clone of CD34+ cells were associated with the level of CCL3 and negatively associated with CCL5, CCL4, PDGF-BB and IL9. Conclusions: This data suggest the existence of apoptotic and PI(3, 4, 5)P3 imbalance in PNH CD34+ cells driven by anti-apoptotic cytokine biosignature in PNH. Plasma cytokines and intracellular enzymes that regulate the phosphoinositide pathways may become a therapeutic target in PNH.