Stem Cell Reports (Jan 2018)
Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages
- Anna-Lena Neehus,
- Jenny Lam,
- Kathrin Haake,
- Sylvia Merkert,
- Nico Schmidt,
- Adele Mucci,
- Mania Ackermann,
- Madline Schubert,
- Christine Happle,
- Mark Philipp Kühnel,
- Patrick Blank,
- Friederike Philipp,
- Ralph Goethe,
- Danny Jonigk,
- Ulrich Martin,
- Ulrich Kalinke,
- Ulrich Baumann,
- Axel Schambach,
- Joachim Roesler,
- Nico Lachmann
Affiliations
- Anna-Lena Neehus
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
- Jenny Lam
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
- Kathrin Haake
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
- Sylvia Merkert
- REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany
- Nico Schmidt
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
- Adele Mucci
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
- Mania Ackermann
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
- Madline Schubert
- REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany
- Christine Happle
- Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany; Department of Paediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany
- Mark Philipp Kühnel
- Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany; Institute for Pathology, Hannover Medical School, 30625 Hannover, Germany
- Patrick Blank
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
- Friederike Philipp
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany
- Ralph Goethe
- Institute for Microbiology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- Danny Jonigk
- Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany; Institute for Pathology, Hannover Medical School, 30625 Hannover, Germany
- Ulrich Martin
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany
- Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
- Ulrich Baumann
- Department of Paediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany
- Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, 02115 Boston, MA, USA
- Joachim Roesler
- Department of Pediatrics, University Clinic Carl Gustav Carus, 01307 Dresden, Germany
- Nico Lachmann
- Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany; REBIRTH Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; Corresponding author
- DOI
- https://doi.org/10.1016/j.stemcr.2017.11.011
- Journal volume & issue
-
Vol. 10,
no. 1
pp. 7 – 16
Abstract
Summary: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNγ) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNγ is the macrophage-activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD-cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNγR1 deficiency and received bone-marrow transplantation. Loss of IFNγR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNγR1 in iMSMD-cohet macrophages abolished IFNγ-dependent phosphorylation of STAT1 and induction of IFNγ-downstream targets such as IRF-1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette-Guérin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNγ signaling in macrophages.
Keywords
