Dysregulated TLR7 signaling drives anemia via development of unique hemophagocyte
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA483019 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2087264.fastq.gz | Fastqsanger.gz | |||
| SRR2087265.fastq.gz | Fastqsanger.gz | |||
| SRR2087266.fastq.gz | Fastqsanger.gz | |||
| SRR2087267.fastq.gz | Fastqsanger.gz | |||
| SRR2087268.fastq.gz | Fastqsanger.gz |
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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. 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
2016-07-01 | E-GEOD-70520 | biostudies-arrayexpress
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
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-07-29 | GSE117718 | GEO
Project description:Dysregulated TLR7 signaling drives anemia via development of hemophagocytic macrophages
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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.
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Project description:Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.
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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.
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Project description:Goal was to detect differences in response to TLR7 versus TLR8 agonists in human monocytes from healthy donors 3 deidentified donors from the Red Cross, monocytes from each donor incubated overnight with either vehicle, TLR7 agonist or TLR8 agonist
2014-12-24 | E-GEOD-64480 | biostudies-arrayexpress