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Dysregulated TLR7 signaling drives anemia via development of hemophagocytic macrophages

ABSTRACT: The debilitating autoimmune disease Systemic Lupus Erythematosus (SLE) is closely associated with Toll-like receptor (TLR) 7 and type I interferon (IFN) activity in humans and in murine SLE-like disease. Two central manifestations of SLE affect the myeloid lineage of the immune system, myeloid expansion and anemia. Yet, whether these symptoms are linked and the role of TLR7 and/or type I IFN in these processes is unclear. Here we show that TLR7 signaling promotes cell-autonomous, phosphoinositide 3-kinase (PI3K)- and mammalian target of rapamycin (mTOR)-dependent macrophage development from the common myeloid progenitor (CMP). Strikingly, this TLR7-driven macrophage development requires and is enhanced by type I IFN. Genome-wide transcriptional profiling and functional studies demonstrated that TLR7 promoted the expression of Spic, the master regulator of splenic red pulp macrophages (RPM) and preferential development of hemophagocytic RPM-like cells from CMP in vitro. We found increased incidence of RPM-like cells in vivo in a mouse model of SLE caused by TLR7 overexpression, which correlated with decreased red blood cell (RBC) count and anemia. These findings demonstrate a mechanism by which TLR7 signaling promotes anemia that is of clinical significance in SLE, other rheumatological diseases and chronic viral infections. This work also identifies a previously unknown molecular pathway by which TLR signaling and type I IFN synergize to promote myeloid development from hematopoietic progenitors. CMP were sorted from the bone marrow of wild-type C57BL/6 mice, cultured with SCF+R848 or SCFr+MCSF, and CD11b+F4/80+ macrophages sorted after 5 days, n=3 per group

ORGANISM(S): Mus musculus

SUBMITTER: Scott Presnell

PROVIDER: E-GEOD-70520 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Dysregulated TLR7 signaling drives anemia via development of hemophagocytic macrophages

Project description:The debilitating autoimmune disease Systemic Lupus Erythematosus (SLE) is closely associated with Toll-like receptor (TLR) 7 and type I interferon (IFN) activity in humans and in murine SLE-like disease. Two central manifestations of SLE affect the myeloid lineage of the immune system, myeloid expansion and anemia. Yet, whether these symptoms are linked and the role of TLR7 and/or type I IFN in these processes is unclear. Here we show that TLR7 signaling promotes cell-autonomous, phosphoinositide 3-kinase (PI3K)- and mammalian target of rapamycin (mTOR)-dependent macrophage development from the common myeloid progenitor (CMP). Strikingly, this TLR7-driven macrophage development requires and is enhanced by type I IFN. Genome-wide transcriptional profiling and functional studies demonstrated that TLR7 promoted the expression of Spic, the master regulator of splenic red pulp macrophages (RPM) and preferential development of hemophagocytic RPM-like cells from CMP in vitro. We found increased incidence of RPM-like cells in vivo in a mouse model of SLE caused by TLR7 overexpression, which correlated with decreased red blood cell (RBC) count and anemia. These findings demonstrate a mechanism by which TLR7 signaling promotes anemia that is of clinical significance in SLE, other rheumatological diseases and chronic viral infections. This work also identifies a previously unknown molecular pathway by which TLR signaling and type I IFN synergize to promote myeloid development from hematopoietic progenitors.

2016-07-01 | GSE70520 | GEO

Bruton's Tyrosine Kinase Regulates TLR9 but not TLR7 Signaling in Human pDCs

Project description:Plasmacytoid dendritic cells (pDCs) can be activated by the endosomal TLRs, and contribute to the pathogenesis of systemic lupus erythematosus (SLE) by producing type I IFNs. Thus, blocking TLR-mediated pDC activation may represent a useful approach for the treatment of SLE. In an attempt to identify a therapeutic target for blocking TLR signaling in pDCs, we investigated the contribution of Bruton's tyrosine kinase (Btk) to the activation of pDCs by TLR7 and TLR9 stimulation by using a selective Btk inhibitor RN486. Stimulation of TLR7 and 9 with their respective agonist, namely, gardiquimod and type A CpG ODN2216, resulted in the activation of human pDCs, as demonstrated by the expression of activation markers (CD69, CD40, and CD86), elevated production of IFN-alpha and other inflammatory cytokines, as well as up-regulation of numerous genes including IFN-alpha-inducible genes and activation of interferon regulatory factor 7 (IRF7) and NF-kB. RN486 inhibited all of these events induced by TLR9, but not TLR7 stimulation, with a nanomolar potency for inhibiting type A CpG ODN2216-mediated production of cytokines (e.g., IC50=386 nM for inhibiting IFN-alpha). Our data reveal Btk as an important regulatory enzyme in the TLR9 pathway, and a potential therapeutic target for SLE and other TLR-driven diseases. pDCs from healthy donors (n=4) were treated with gardiquimod (TLR7 agonist) or ODN 2216 (TLR9 agonist) with or without BTK inhibitor for 3 hours.

2015-10-24 | E-GEOD-41825 | biostudies-arrayexpress

Differential gene expression of TLR7 overexpressing inflammatory hemophagocytes, Ly6Chi Monocytes, and Red Pulp Macrophages

Project description:We have defined a novel population of monocyte-derived hemophagocytes (inflammatory hemophagocytes (iHPC)) found in situations of inflammation, such as TLR7.1 mice that overexpress TLR7. These iHPC are similar yet distinct from red pulp macrophages (RPM) and differentiate in response to chronic TLR7 signals. In vivo, iHPC phagocytose red blood cells and platelets causing anemia and thrombocytopenia. We performed this study to further understand iHPC and their relationship to RPM and monocytes and determine what gene signatures make them unique.

2019-01-15 | GSE117711 | GEO

RNA-seq of in vitro derived B cells

Project description:IFN-γ has been reported to be the ABC-promoting cytokine combined with signaling from IL-21, CD40L, Ag-BCR and TLR7 agonist. Hence, we adopted the in vitro differentiation cocktails (anti-IgM, R848, anti-CD40, IL-21 plus IFN-γ or IL-4) to determine the role of IFN-γ in ABC differentiation. Mouse splenic B cells were purified by negative selection and cultured in the presence of the above cocktails. Compared with IL-4, IFN-γ-polarized cells preferentially differentiated to ABC-like cells. And RNA-seq were performed on IFN-γ-polarized cells and IL-4-polarized cells.

2023-02-17 | E-MTAB-12569 | biostudies-arrayexpress

UNC93B1 variants underlie TLR7-dependent autoimmunity

Project description:UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

2023-12-14 | GSE250223 | GEO

Bulk RNA Sequencing of XIST-knockdown A431 Cells

Project description:Systemic Lupus Erythematosus (SLE) is among the most sex-biased autoimmune diseases identified to date, affecting 9-times more women than men. Recognition of self-RNA by Toll-like receptor 7 (TLR7) is implicated as a central pathogenic process leading to the aberrant production of type-I interferon (IFN) in SLE, but the specific RNA molecules contributing to this process have not been defined. Given the role of self-RNA and biological sex in SLE pathogenesis, we investigated which sex-biased self-RNAs are potentially responsible for aberrant TLR7 activation in SLE. We used recent revelations about TLR7 sequence specificity and publicly available RNA sequencing data to identify sex-biased sources of self-RNA containing TLR7 ligands. We found X-inactive specific transcript (XIST) to be a particularly rich source of TLR7 ligands that is specifically expressed in women. We then investigated the capacity of XIST to act as a TLR7 ligand in vitro and found that multiple fragments of XIST induce IFNα production in a TLR7-dependent manner more than control RNA of equal length. Furthermore, we found that RNA isolated from XIST-knockout cells have significantly reduced capacity to stimulate TLR7 compared to RNA from wild-type cells. Finally, we used flow cytometry and publicly available RNA sequencing data to investigate the connection between XIST and SLE disease variables. We found that higher XIST expression correlated with SLE disease status, higher SLE disease activity index (SLEDAI) scores, and the interferon signature. Our data suggest that XIST is a source of TLR7 ligands that may underlie the sex bias in SLE.

2023-11-15 | GSE201160 | GEO

Molecular Dissection of Disease Heterogeneity in SLE

Project description:Systemic lupus erythematosus (SLE) affects 1 in 537 of African American (AA) women, which is >2-fold more than European American (EA) women. AA patients also develop the disease at a younger age, have more severe symptoms, and a greater chance of early mortality. We used a multi-omics approach to uncover ancestry-specific immune alterations in SLE patients and healthy controls that may contribute to disease disparities. Cell composition, signaling, and epigenetics were evaluated by mass cytometry; droplet-based single cell transcriptomics and paired proteogenomics (scRNA-Seq/scCITE-Seq). Soluble mediator levels were measured in plasma and stimulated whole blood. TLR3/4/7/8/9 gene expression pathways in B cells and monocytes were enhanced in AA SLE patients compared to EA patients. TLR7/8/9 and IFN phospho-signaling responses were also heightened in healthy AA versus EA controls. Exposure of AA and EA healthy control cells to TLR7/8/9 agonists or IFN resulted in altered immune cell compositions that recapitulated the ancestry-associated differences in SLE patients. These data support that ancestry-based differences in TLR7/8, TLR9, and IFN responses that can be detected in healthy individuals could influence lupus disease course and severity.

2023-10-11 | GSE189050 | GEO

Bruton's Tyrosine Kinase Regulates TLR9 but not TLR7 Signaling in Human pDCs

2015-10-24 | GSE41825 | GEO

Leukocyte subset-specific type 1 interferon signatures in SLE and other immune-mediated diseases.

Project description:Objectives Type 1 interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE), but most studies have only reported the effect of IFN-I on mixed cell populations. We aimed to define modules of IFN-I associated genes in purified leukocyte populations and use these as a basis for a detailed comparative analysis. Methods CD4+ and CD8+ T-cells, monocytes and neutrophils were purified from patients with SLE, other immune-mediated diseases and healthy volunteers (HV)and gene expression determined by microarray. Modules of IFN-I associated genes were defined using weighted gene coexpression network analysis. The composition and expression of these modules was analysed. Results 1,150 of 1,288 IFN-I associated genes were specific to myeloid subsets, compared with 11 genes unique to T-cells. IFN-I genes were more highly expressed in myeloid subsets compared to T-cells. A subset of neutrophil samples from HV and conditions not classically associated with IFN-I signatures displayed increased IFN-I gene expression, whereas upregulation of IFN-I associated genes in T-cells was restricted to SLE. Conclusions Given the broad upregulation of IFN-I genes in neutrophils including in some HV, investigators reporting IFN-I signatures on the basis of whole blood samples should be cautious about interpreting this as evidence of bona fide IFN-I mediated pathology. Instead, specific upregulation of IFN-I associated genes in T-cells may be a useful biomarker and a further mechanism by which elevated IFN-I contributes to autoimmunity in SLE.

2016-06-01 | E-MTAB-2713 | biostudies-arrayexpress

Gene expression analysis in the spleen of wild type, Sle1.3 (lupus mice) and Sle1.3 mice haplodeficient for E2-2 (exhibiting non functional pDCs)

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition and tissue inflammation such as glomerulonephritis. Innate recognition of molecular complexes containing self-DNA and RNA and the ensuing production of type I interferons (IFN) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a relevant source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question using haplodeficiency of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that Tcf4+/- animals were significantly protected from SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. The protection was also observed after the monoallelic deletion of Tcf4 specifically in the dendritic cell lineage. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE ameliorated key disease manifestations including anti-DNA antibody production, immune activation and glomerulonephritis. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis, confirming their potential utility as therapeutic targets in the disease. Cellluar suspension were obtained from the spleen of wild type, Sle1.3 and Sle1.3/E2-2het mice. 10 million of cells were used to isolate RNA from each sample. After RNA isolation a microarray analysis using the Ambion WT labeling kit was done. Expression was analyzed using Affymetrix Mouse Gene 1.0 ST. 2 Wild type mice, 3 Sle1.3 and 3 Sle1.3/E2-2 het mice were used for the analysis.

2014-07-30 | E-GEOD-57324 | biostudies-arrayexpress

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