Maren Weisser1, Uta M Demel2, Stefan Stein1, Linping Chen-Wichmann1, Fabien Touzot3, Giorgia Santilli4, Stefanie Sujer5, Christian Brendel1, Ulrich Siler6, Marina Cavazzana3, Adrian J Thrasher4, Janine Reichenbach6, Marieke A G Essers2, Joachim Schwäble7, Manuel Grez8. 1. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany. 2. 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. 3. Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. 4. Section of Molecular and Cellular Immunology, UCL Institute of Child Health, London, United Kingdom. 5. Junior Research Group "Hematopoietic Stem Cells and Stress," German Cancer Research Center (DKFZ), INF280, Heidelberg, Germany. 6. Division of Immunology, University Children's Hospital, and Children's Research Centre Zürich, Zurich, Switzerland. 7. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany; Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany. 8. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany. Electronic address: grez@gsh.uni-frankfurt.de.
Abstract
BACKGROUND: 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. OBJECTIVE: 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). METHODS: We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. OBJECTIVE: 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). METHODS: We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD. RESULTS: 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. CONCLUSIONS: 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: Mark S Gresnigt; Katharina L Becker; Floris Leenders; M Fernanda Alonso; Xiaowen Wang; Jacques F Meis; Judith M Bain; Lars P Erwig; Frank L van de Veerdonk Journal: J Innate Immun Date: 2017-12-16 Impact factor: 7.349
Authors: Shayda Hemmati; Taneisha Sinclair; Meng Tong; Boris Bartholdy; Rachel O Okabe; Kristina Ames; Leanne Ostrodka; Tamanna Haque; Imit Kaur; Taylor S Mills; Anupriya Agarwal; Eric M Pietras; Jean J Zhao; Thomas M Roberts; Kira Gritsman Journal: JCI Insight Date: 2019-05-23