Journal
JOURNAL OF IMMUNOLOGY
Volume 200, Issue 4, Pages 1434-1442Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1701120
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Funding
- Comissao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) Computational Biology [23038.010048/2013-27]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico Universal [473897/2013-0]
- Academy of Medical Sciences/U.K. [NAF004/1005]
- CAPES
- Conselho Nacional de Pesquisas (CNPq)
- National Institutes of Health Global Research Initiative Program [TW008276]
- Howard Hughes Medical Institute ECS [55007412]
- CAPES/ESE
- Isaac Newton Trust/Wellcome Trust Institutional Strategic Support Fund/University of Cambridge research grant
- Wellcome Trust [201946/Z/16/Z]
- Agentschap Innoveren en Ondernemen [IWT141614]
- CAPES (PVE)
- FWO [G0D6817N]
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IFN-stimulated gene 15 (ISG15) deficiency in humans leads to severe IFNopathies and mycobacterial disease, the latter being previously attributed to its extracellular cytokine-like activity. In this study, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to primary human monocytes. A balanced ISG15-induced monocyte/IL-10 versus lymphoid/IFN-gamma expression, correlating with p38 MAPK and PI3K signaling, was found using targeted in vitro and ex vivo systems analysis of human transcriptomic datasets. The specificity and MAPK/PI3K-dependence of ISG15-induced monocyte IL-10 production was confirmed in vitro using CRISPR/Cas9 knockout and pharmacological inhibitors. Moreover, this ISG15/IL-10 axis was amplified in leprosy but disrupted in human active tuberculosis (TB) patients. Importantly, ISG15 strongly correlated with inflammation and disease severity during active TB, suggesting its potential use as a biomarker, awaiting clinical validation. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB.
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