Biology subjects

Mansur, D. S.

Publications and source records attributed to Mansur, D. S..

3 recordsLinked to original sources

bioRxiv2018

Vasculature-associated adipose tissue macrophages dynamically adapt to inflammatory and metabolic challenges

Tissue-resident macrophages comprise the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophage populations change during metabolic stress and ageing, and are thought to contribute to the pathogenesis of obesity. Here, we studied adipose tissue macrophage subpopulations in the steady state, and in response to nutritional and infectious challenges.\n\nUsing comprehensive cell-surface-based and gene expression analyses, we found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying a very high endocytic capacity. We refer to these cells as Vasculature-associated Adipose tissue Macrophages (VAMs). Chronic high fat diet (HFD) feeding results in the accumulation of a monocyte-derived CD11c+CD64+ double positive (DP) macrophage eWAT population with a predominant anti-inflammatory gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that adipose tissue macrophage populations adapt to metabolic stress and inflammation, suggesting an important role for these cells in restoring homeostasis.

immunology↗

bioRxiv2018

IFIT3 and IFIT2/3 promote IFIT1-mediated translation inhibition by enhancing binding to non-self RNA.

Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed during the cell-intrinsic immune response to viral infection. IFIT1 inhibits translation by binding directly to the 5' end of foreign RNAs, particularly those with non-self cap structures, precluding the recruitment of the cap-binding eukaryotic translation initiation factor 4F and subsequent 40S recruitment. Interaction of different IFIT family members is well described, but little is known of the molecular basis of IFIT association or its impact on function. Here, we reconstituted different complexes of IFIT1, IFIT2 and IFIT3 in vitro, which enabled us to reveal critical aspects of IFIT complex assembly. IFIT1 interacts rapidly and strongly with IFIT3 forming a stable heterotetramer. IFIT2 and IFIT3 homodimers dissociate to form a more stable heterodimer that associates with IFIT1, forming an IFIT1:IFIT2:IFIT3 trimer. Site-directed mutagenesis revealed a C-terminal YxxxL motif in IFIT1 that mediates its association with IFIT3. Using various reporter mRNAs, we demonstrate for the first time that IFIT3 stabilises IFIT1 binding to cap0-mRNA and enhances its translation inhibition activity. Disrupting the binding interface between IFIT1 and IFIT3 abrogated this enhancement. This work reveals molecular aspects of IFIT assembly and provides an important missing link between IFIT interaction and function.

immunology↗

bioRxiv2017

ISG15 induces IL-10 production in human monocytes and is a biomarker of disease severity during active tuberculosis

Interferon stimulated gene 15 (ISG15) deficiency in humans leads to severe interferonopathies and mycobacterial disease, the latter being previously associated to its extracellular cytokine-like activity. Here, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to human primary monocytes. Employing ex vivo systems analysis of human transcriptome datasets, we observed a significant correlation of ISG15-induced monocyte IL-10 and lymphocyte IFN{gamma} balanced expression. This effect was associated with p38 MAPK and PI3K signalling in healthy volunteers. 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/IL10 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. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB, revealing a potential biomarker for disease severity in this major human disease.

immunology↗