Abstract
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage. Diverse host receptors are required to control the formation and resolution of granuloma, but little is known concerning their regulatory interactions. Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production. In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution. Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.
Highlights
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage
Macrophage-inducible C-type lectin (Mincle) is essential for proinflammatory stimulation by enhancing NFkB signalling, and for the translational control of specific transcripts required for nitric oxide (NO) production and inflammation resolution in macrophages
To examine the crosstalk between the Toll-like receptors (TLRs) and Mincle signalling pathways, wild type (WT) and Mincle À / À macrophages were stimulaed with their respective ligands, and their regulatory interactions were examined by transcriptome analysis
Summary
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage. Diverse host receptors are required to control the formation and resolution of granuloma, but little is known concerning their regulatory interactions. In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution. Human Mincle degrades interferon regulatory factor 1 by activating the E3 ubiquitin-protein ligase Mdm[2], thereby suppressing IL12A transcription These observations demonstrate that two roles of Mincle, stimulation and resolution of inflammation, allow crosstalk with other receptor signalling events to achieve balanced immune responses. Mincle is essential for proinflammatory stimulation by enhancing NFkB signalling, and for the translational control of specific transcripts required for NO production and inflammation resolution in macrophages
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