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Tuberculosis-associated IFN-I induces Siglec-1 on microtubule-containing tunneling nanotubes and favors HIV-1 spread in macrophages

ABSTRACT: To understand the susceptbility of human M(IL-10) macrophages to human immunodeficiency virus, we performed a genome-wide transcriptome analysis in these cells to identify a gene profile responsible for this phenomenon. A distinct 60 gene-transcript signature was defined in M(IL-10) macrophages, using a combination of the expression level, statistical filters and hierarchical clustering; 51 genes were up-regulated and 9 genes were down-regulated in M(IL-10) macrophages compared to control cells. Among the genes upregulated, we identified a interferon-stimulated gene (ISG) signature include SIGLEC-1. We confirmed SIGLEC-1 and other five ISG genes by qPCR, FACS and western blot.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139511 | GEO | 2020/04/04

REPOSITORIES: GEO

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Project description:Siglec-E is a murine CD33-related siglec that functions as an inhibitory receptor and is expressed mainly on neutrophils and macrophage populations. Recent studies have suggested that siglec-E is an important negative regulator of LPS-TLR4 signalling and one report (Wu et al 2016) claimed that siglec-E is required for TLR4 endocytosis following uptake of Escherichia coli by macrophages and dendritic cells (DCs). Our attempts to reproduce these observations using cells from wildtype (WT) and siglec E deficient mice were unsuccessful. We used a variety of assays to determine if siglec-E expressed by different macrophage populations can regulate TLR-4 signalling in response to LPS, but found no consistent differences in cytokine secretion in vitro and in vivo, comparing 3 different strains of siglec-E-deficient mice with matched WT controls. No evidence was found that the siglec-E deficiency was compensated by expression of siglecs-F and –G, the other murine inhibitory CD33-related siglecs. Quantitative proteomics was used as an unbiased approach and provided additional evidence that siglec-E does not suppress inflammatory TLR4 signaling. Interestingly, proteomics revealed a siglec E dependent alteration in macrophage phenotype that could be relevant to functional responses in host defence. In support of this, siglec-E-deficient mice exhibited enhanced growth of Salmonella enterica serovar Typhimurium in the liver following intravenous infection, but macrophages lacking siglec-E did not show altered uptake or killing of bacteria in vitro. Using various cell types including bone marrow derived DCs (BMDC), splenic DCs and macrophages from WT and siglec-E-deficient mice, we showed that siglec-E is not required for TLR4 endocytosis following E.coli uptake or LPS challenge. We failed to see expression of siglec-E by BMDC even after LPS-induced maturation, but confirmed previous studies that splenic DCs express low levels of siglec-E. Taken together, our findings do not support a major role of siglec-E in regulation of TLR4 signalling functions or TLR4 endocytosis in macrophages or DCs. Instead, they reveal that induction of siglec-E by LPS can modulate the phenotype of macrophages, the functional significance of which is currently unclear.

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Tuberculosis-associated IFN-I induces Siglec-1 on microtubule-containing tunneling nanotubes and favors HIV-1 spread in macrophages

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