Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus

• Published in: Annals of the rheumatic diseases Vol. 79; no. 2; pp. 242 - 253
• Main Authors: Grigoriou, Maria, Banos, Aggelos, Filia, Anastasia, Pavlidis, Pavlos, Giannouli, Stavroula, Karali, Vassiliki, Nikolopoulos, Dionysis, Pieta, Antigone, Bertsias, George, Verginis, Panayotis, Mitroulis, Ioannis, Boumpas, Dimitrios T
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.02.2020; Elsevier Limited; BMJ Publishing Group
• Subjects: Adaptation; Animals; Apoptosis; Apoptosis - immunology; autoimmunity; Blood; Bone marrow; c-Kit protein; CCAAT-Enhancer-Binding Protein-delta - metabolism; CCAAT-Enhancer-Binding Proteins - metabolism; CD34 antigen; Cell activation; Cell adhesion & migration; Cell cycle; Cell Cycle - immunology; Cell differentiation; Cell proliferation; Cellular Reprogramming - immunology; Chemokines; Chromosome Mapping; Cytokines; DNA Damage; Epigenetics; Flow Cytometry; Fluorescent Antibody Technique; Gene expression; Granulocyte Colony-Stimulating Factor - metabolism; Granulocytes; Granulocytes - immunology; Granulopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - immunology; Immunofluorescence; Immunology; Inflammation; Leukocytes (neutrophilic); Lupus; Lupus Erythematosus, Systemic - immunology; Lymphocytes - immunology; Mice; Myeloid Cells - immunology; Myelopoiesis; Neutrophils; Pathogenesis; Phase transitions; Progenitor cells; Ribonucleic acid; RNA; Stem cells; Systemic Lupus Erythematosus; Transcription activation; Transcriptome - immunology; Transcriptomics; Greece; autoimmunity; inflammation; systemic lupus erythematosus
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2019-215782

ObjectivesHaematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs.MethodsA global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence.ResultsTranscriptomic analysis of Lin−Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe, Cebpd and Csf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data.ConclusionsAberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare.Trial registration number4948/19-07-2016.