title: Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions.
abstract: Defects in phagocytic nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) function cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by dysfunctional microbicidal activity and chronic inflammation.
  
  
  
  We sought to study the effect of chronic inflammation on the hematopoietic compartment in patients and mice with X-linked chronic granulomatous disease (X-CGD).
  
  
  
  We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD.
  
  
  
  An analysis of bone marrow cells from patients and mice with X-CGD revealed a dysregulated hematopoiesis characterized by increased numbers of hematopoietic progenitor cells (HPCs) at the expense of repopulating hematopoietic stem cells (HSCs). In patients with X-CGD, there was a clear reduction in the proportion of HSCs in bone marrow and peripheral blood, and they were also more rapidly exhausted after in vitro culture. In mice with X-CGD, increased cycling of HSCs, expansion of HPCs, and impaired long-term engraftment capacity were found to be associated with high concentrations of proinflammatory cytokines, including IL-1β. Treatment of wild-type mice with IL-1β induced enhanced cell-cycle entry of HSCs, expansion of HPCs, and defects in long-term engraftment, mimicking the effects observed in mice with X-CGD. Inhibition of cytokine signaling in mice with X-CGD reduced HPC numbers but had only minor effects on the repopulating ability of HSCs.
  
  
  
  Persistent chronic inflammation in patients with CGD is associated with hematopoietic proliferative stress, leading to a decrease in the functional activity of HSCs. Our observations have clinical implications for the development of successful autologous cell therapy approaches.
authors: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors: Maren
authors: M
authors: Weisser
authors: Junior Research Group "Hematopoietic Stem Cells and Stress," German Cancer Research Center (DKFZ), INF280, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), INF280, Heidelberg, Germany.
authors: Uta M
authors: UM
authors: Demel
authors: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors: Stefan
authors: S
authors: Stein
authors: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors: Linping
authors: L
authors: Chen-Wichmann
authors: Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors: Fabien
authors: F
authors: Touzot
authors: Section of Molecular and Cellular Immunology, UCL Institute of Child Health, London, United Kingdom.
authors: Giorgia
authors: G
authors: Santilli
authors: Junior Research Group "Hematopoietic Stem Cells and Stress," German Cancer Research Center (DKFZ), INF280, Heidelberg, Germany.
authors: Stefanie
authors: S
authors: Sujer
authors: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
authors: Christian
authors: C
authors: Brendel
authors: Division of Immunology, University Children's Hospital, and Children's Research Centre Zürich, Zurich, Switzerland.
authors: Ulrich
authors: U
authors: Siler
authors: Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors: Marina
authors: M
authors: Cavazzana
authors: Section of Molecular and Cellular Immunology, UCL Institute of Child Health, London, United Kingdom.
authors: Adrian J
authors: AJ
authors: Thrasher
authors: Division of Immunology, University Children's Hospital, and Children's Research Centre Zürich, Zurich, Switzerland.
authors: Janine
authors: J
authors: Reichenbach
authors: Junior Research Group "Hematopoietic Stem Cells and Stress," German Cancer Research Center (DKFZ), INF280, Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), INF280, Heidelberg, Germany.
authors: Marieke A G
authors: MAG
authors: Essers
authors: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany; Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
authors: Joachim
authors: J
authors: Schwäble
authors: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany. Electronic address: grez@gsh.uni-frankfurt.de.
authors: Manuel
authors: M
authors: Grez
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers; D016022:Case-Control Studies; D002452:Cell Count; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D006085:Graft Survival; D006105:Granulomatous Disease, Chronic / Q000209:etiology / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010641:Phenotype; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Chronic granulomatous disease; IL-1β; anakinra; cell cycle; competitive repopulation assay; dysfunctional hematopoiesis; engraftment defect; gene therapy; hematopoietic stem cell; hyperinflammation