DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria

Killy B, Bodendorfer B, Mages J, Ritter K, Schreiber J, Hölscher C, Pracht K, Ekici AB, Jäck HM, Lang R (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Life Science Alliance Life Science Alliance

Book Volume: 4

Journal Issue: 6

DOI: 10.26508/lsa.202000810

Abstract

The mycobacterial cell wall glycolipid trehalose-6,6-dimycolate (TDM) activates macrophages through the C-type lectin receptor MINCLE. Regulation of innate immune cells relies on miRNAs, which may be exploited by mycobacteria to survive and replicate in macrophages. Here, we have used macrophages deficient in the microprocessor component DGCR8 to investigate the impact of miRNA on the response to TDM. Deletion of DGCR8 in bone marrow progenitors reduced macrophage yield, but did not block macrophage differentiation. DGCR8-deficient macrophages showed reduced constitutive and TDM-inducible miRNA expression. RNAseq analysis revealed that they accumulated primary miRNA transcripts and displayed a modest type I IFN signature at baseline. Stimulation with TDM in the absence of DGCR8 induced overshooting expression of IFNβ and IFN-induced genes, which was blocked by antibodies to type I IFN. In contrast, signaling and transcriptional responses to recombinant IFNβ were unaltered. Infection with live Mycobacterium bovis Bacille Calmette-Guerin replicated the enhanced IFN response. Together, our results reveal an essential role for DGCR8 in curbing IFNβ expression macrophage reprogramming by mycobacteria.

Authors with CRIS profile

Barbara Killy Professur für Mikrobiologie Katharina Pracht Department of Molecular Immunology Arif Bülent Ekici Institute of Human Genetics Hans-Martin Jäck Department of Molecular Immunology Roland Lang Professur für Angeborene Immunität und Pathogenerkennung

Involved external institutions

Forschungszentrum Borstel - Leibniz-Zentrum für Medizin und Biowissenschaften / Research Center Borstel - Leibniz-Center for Medicine and Biosciences DE Germany (DE)

How to cite

APA:

Killy, B., Bodendorfer, B., Mages, J., Ritter, K., Schreiber, J., Hölscher, C.,... Lang, R. (2021). DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria. Life Science Alliance, 4(6). https://dx.doi.org/10.26508/lsa.202000810

MLA:

Killy, Barbara, et al. "DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria." Life Science Alliance 4.6 (2021).

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