RT Journal Article
SR Electronic
T1 DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000810
DO 10.26508/lsa.202000810
VO 4
IS 6
A1 Barbara Killy
A1 Barbara Bodendorfer
A1 Jörg Mages
A1 Kristina Ritter
A1 Jonathan Schreiber
A1 Christoph Hölscher
A1 Katharina Pracht
A1 Arif Ekici
A1 Hans-Martin Jäck
A1 Roland Lang
YR 2021
UL https://www.life-science-alliance.org/content/4/6/e202000810.abstract
AB 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.