Impaired IFNg-signaling and mycobacterial clearance in IFNgR1-deficient human iPSC-derived macrophages
Autor: | Nico Lachmann, Joachim Roesler, Ulrich Baumann, Ulrich Martin, Anna-Lena Neehus, Sylvia Merkert, Madline Schubert, Mark P. Kühnel, Patrick Blank, Christine Happle, Adele Mucci, Danny Jonigk, Ulrich Kalinke, Nico Schmidt, Axel Schambach, Ralph Goethe, Kathrin Haake, Jenny Lam, Friederike Philipp, Mania Ackermann |
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Přispěvatelé: | Publica, TWiNCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH, Feodor-Lynen-Str.7, 30625 Hannover, Germany. |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
mycobacteria Induced Pluripotent Stem Cells macrophage Compound heterozygosity Biochemistry 03 medical and health sciences Interferon-gamma Downregulation and upregulation Immunity Report Genetics medicine Humans Interferon gamma Genetic Predisposition to Disease BCG STAT1 Induced pluripotent stem cell lcsh:QH301-705.5 IFNγR1 Receptors Interferon lcsh:R5-920 iPSC biology Macrophages Cell Biology Mycobacterium bovis hematopoiesis Transplantation MSMD Haematopoiesis 030104 developmental biology lcsh:Biology (General) Immunology IFNgR1 biology.protein lcsh:Medicine (General) Developmental Biology medicine.drug Signal Transduction |
Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 10, Iss 1, Pp 7-16 (2018) |
Popis: | 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. Graphical Abstract Highlights • Generation of patient-specific iPSCs from small volume (7 mL) peripheral blood • Heterozygous or compound heterozygous iPSCs from one chimeric MSMD patient • Patient-specific iPSC macrophages reveal impaired IFNγ downstream signaling • Compound heterozygous macrophages show decreased killing of mycobacteria Neehus and colleagues describe the simultaneous generation of genetically diverse patient-specific iPSC lines from one chimeric patient with Mendelian susceptibility to mycobacterial disease (MSMD) due to IFNγR1 deficiency. Hematopoietic differentiation toward macrophages of heterozygous and compound heterozygous MSMD iPSC lines laid the foundation to study IFNγ signaling and susceptibility to mycobacterial infections of patient-derived macrophages. |
Databáze: | OpenAIRE |
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