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Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages.
Neehus, Anna-Lena Lam, Jenny Haake, Kathrin Merkert, Sylvia Schmidt, Nico Mucci, Adele Ackermann, Mania Schubert, Madline Happle, Christine Kühnel, Mark Philipp
Neehus, Anna-Lena
Lam, Jenny
Haake, Kathrin
Merkert, Sylvia
Schmidt, Nico
Mucci, Adele
Ackermann, Mania
Schubert, Madline
Happle, Christine
Kühnel, Mark Philipp
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2018-01-09
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Abstract
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.
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Impaired IFNγ-Signaling and Mycobacterial Clearance in IFNγR1-Deficient Human iPSC-Derived Macrophages. 2018, 10 (1):7-16 Stem Cell Reports
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en
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2213-6711