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

• Published in: Cytokine (Philadelphia, Pa.) Vol. 150; p. 155780
• Main 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2022
• Subjects: Apoptosis; Chemokines; Cytokines; Hematopoietic stem/progenitor cells; Paroxysmal nocturnal hemoglobinuria; Phosphatidylinositol (3,4,5)-trisphosphate; PDGFR-β; GPI; CCL3 or MIP-1α; PIP5Kα; Spl; CCL2 or MCP-1; IFN-γ; CCL5 or RANTES; PI3K; FLAER; Hematopoietic stem/progenitor cells; PI(3,4,5)P3; CCL4 or MIP-1β; Cytokines; VEGF; Strom; GPR75; LyNo; Paroxysmal nocturnal hemoglobinuria; PI(4,5)P2; CXCL10 or IP-10; TNF-α; IL1ra; PI4K; PDGF; PIP; Phosphatidylinositol (3,4,5)-trisphosphate; HPCs; Basic FGF or FGF-2; Chemokines; Apoptosis
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2021.155780

[Display omitted] •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. 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. 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. 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. 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.