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Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

ABSTRACT: Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-Î± in vitro and that Siglec-H ko mice produce more IFN-Î± after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed

ORGANISM(S): Mus musculus

SUBMITTER: Heike Schmitt

PROVIDER: E-GEOD-79248 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Type-I interferon inducible genes 26 weeks after mCMV infection in Siglec-H wt and Siglec-H ko mice and their non infected controls

Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.

2016-03-16 | GSE79248 | GEO

Gene expression profiles of splenic pDCs in C57Bl6/J and Siglec-H deficient mice

Project description:The steady-state gene expression of pDCs of two different mouse strains was analyzed. Splenic plasmacytoid dendritic cells (pDCs) of Siglec-H knock-out mice on C57Bl& background and the Siglec-H expression littermates (+/+) were enriched and sorted by FACS before generating RNA, followed by cDNA generation and sequencing.

2021-09-15 | GSE179840 | GEO

Human primary macrophages derived in vitro from circulating monocytes comprise adherent and non-adherent subsets with differential expression of Siglec-1 and CD4 and permissiveness to HIV-1 infection

Project description:Macrophages are a major target for human immunodeficiency virus type 1 (HIV-1) infection. However, macrophages are largely heterogeneous and may exhibit differences in permissiveness to HIV-1 infection. This study highlights the interplay of macrophage heterogeneity in HIV-1 pathogenesis. We show that monocyte-derived macrophages (MDM) could be divided into two distinct subsets: CD14+Siglec-1hiCD4+ (non-adherent MDM), and CD14+Siglec-1LoCD4- (adherent MDM). The CD14+Siglec-1hiCD4+MDM subset represented the smaller proportion in the macrophage pool, and varied among different donors. Fractionation and subsequent exposure of the two MDM subsets to HIV-1 revealed opposite outcomes in terms of HIV-1 capture and infection. Although the CD14+Siglec-1hiCD4+MDM captured significantly more HIV-1, infection was significantly higher in the CD14+Siglec-1LoCD4-MDM subset. Thus, CD14+Siglec-1hiCD4+MDM were less permissive to infection. Depletion of CD14+Siglec-1hiCD4+MDM or a decrease in their percentage, resulted in increased infection of MDM, suggestive of a capacity of these cells to capture and sequester HIV-1 in an environment that hinders its infectivity. Increased expression of innate restriction factors and cytokine genes were observed in the non-adherent CD14+Siglec-1hiCD4+MDM, both before and after HIV-1 infection, compared to the adherent CD14+Siglec-1LoCD4-MDM. The differential expression of gene expression profiles in the two macrophage subsets may provide an explanation for the differences observed in HIV-1 infectivity.

2018-02-22 | GSE103666 | GEO

Proximity labeling of Siglec-1 counter-receptors on activated regulatory T cells using soluble Siglec-1-HRP multimers

Project description:Siglec-1 is a macrophage lectin-like receptor that mediates sialic acid-dependent cellular interactions. It was shown previously to promote inflammation in autoimmune disease through suppressing the expansion of regulatory T cells (Tregs). We have investigated the molecular basis for Siglec-1 binding to these cells using in vitro-induced Tregs. A proximity labelling and proteomics strategy were used to identify glycoproteins expressed by activated Tregs that may function as Siglec-1 counter-receptors.

2021-04-28 | PXD021693 | Pride

Proximity labeling of Siglec-1 counter-receptors on activated regulatory T cells using Siglec-1-HRP multimers on nano-beads

2021-04-28 | PXD021691 | Pride

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

Project description: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.

2020-04-04 | GSE139511 | GEO

Plasmacytoid dendritic cell precursors give rise to conventional dendritic cells via a Siglec-H+ Zbtb46+ Ly6D+ intermediary stage

Project description:Plasmacytoid and conventional dendritic cells (pDC, and cDC) are generated from distinct lymphoid and myeloid progenitor cells in murine bone marrow. Despite the early separation of pDC and cDC lineages, CD11c+ MHCII-/lo Siglec-H+ CCR9lo pDC-like precursor cells are able to differentiate into both pDC and cDC. Single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis revealed the heterogeneity and commitment of subsets in this compartment. While Ly6D– cells within this fraction were cDC-committed and B220hi Ly6Dhi Zbtb46– cells were immediate precursors of pDCs, B220lo Ly6Dhi Zbtb46– cells still had the potential to generate cDCs in addition to pDCs. Transition to cDCs occurred via an intermediary stage marked by coexpression of Siglec-H, Ly6D and Zbtb46. Type I IFN stimulation limited cDC and promoted pDC output from these precursors, demonstrating their plasticity in response to inflammation. Thus, flexibility to divert to cDCs is retained in the pDC lineage at later differentiation stages.

2021-12-01 | GSE189780 | GEO

A commensal Clostridium bacteria restricts alphavirus dissemination through a bile acid-type I IFN signaling axis

Project description:The emerging alphavirus chikungunya virus (CHIKV) has infected millions of people. However, the factors modulating disease outcome remain poorly understood. We show that depletion of the gut microbiota in oral antibiotic-treated or germ-free mice leads to greater CHIKV infection and spread within one day of virus inoculation. Perturbation of the gut microbiota alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single commensal bacterial species, Clostridium scindens, or its derived metabolite, the bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, commensal gut bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects virus dissemination and potentially, epidemic spread 3 biological replicates were processed per time point and group

2020-06-09 | GSE152043 | GEO

A commensal Clostridium bacteria restricts alphavirus dissemination through a bile acid-type I IFN signaling axis

2020-05-13 | GSE150387 | GEO

Chronic Activation of pDCs in Autoimmunity is linked to Dysregulated ER Stress and Metabolic Responses

Project description:Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in multiple autoimmune diseases, such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Here, we report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits the production of IFN-α by TLR7- or TLR9-activated pDCs. In SSc patients, pDCs demonstrated reduced expression of UPR marker genes, which inversely correlated with the levels of IFN-I-stimulated genes. CXCL4, a chemokine that is elevated in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation and cAMP signaling, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.

2022-08-15 | GSE211230 | GEO

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