PLX040328

GSE149441: RNAseq analysis of resting and TDM-stimulated DGCR8-deficient macrophages

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Pathogenic mycobacteria subvert immune responses to survive and replicate in macrophages. Mycobacterial cell wall components are sensed by several C-type lectin receptors, including MINCLE, the receptor for the cord factor trehalose-6,6-dimycolate (TDM). Regulation of innate immune cells relies on miRNAs, some of which are induced by mycobacterial ligands. Thus, MTB may exploit host miRNAs to establish its niche in macrophages. Here, we have employed conditional knockout mice for the microprocessor component DGCR8 to investigate the impact of miRNAs on the macrophage response to the mycobacterial cord factor. Deletion of DGCR8 during differentiation of macrophages from bone marrow progenitors significantly reduced the cell yield, but did not interfere with macrophage differentiation as determined by typical surface marker expression and phagocytic capacity. DGCR8-deficient macrophages expressed reduced levels of constitutive and TDM-inducible miRNAs, yet in turn accumulated primary miRNA transcripts. RNAseq revealed a modest type I interferon (IFN) signature in resting DGCR8-deficient macrophages. Stimulation of DGCR8-deficient macrophages with TDM induced overshooting and prolonged expression of interferon response genes, which was associated with enhanced expression of IFNb and could be largely prevented by antibodies to type I interferon. In turn, exogenous IFNb upregulated CXCL10 and CD69 to similar levels in control and DGCR8-deficient macrophages, indicating that signaling downstream of the type I IFN receptor was unaltered. Infection with live Mycobacterium bovis Bacille Calmette-Guerin (BCG) replicated the enhanced interferon response of DGCR8-deficient macrophages. Together, our results reveal an essential role for DGCR8 in curbing IFNb expression and IFN-dependent macrophage activation by mycobacteria. SOURCE: Steffen Uebe (steffen.uebe@uk-erlangen.de) - Universitaetsklinikum Erlangen