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Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE112542 | GEO | 2019/08/12

REPOSITORIES: GEO

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Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88

Project description:Innate immune cells, and myeloid lineage cells in particular, constitute the first line ofdefense for the containment of invading pathogens. To meet the augmented demand of myeloidcells in response to systemic infections, inflammatory signals trigger a rapid transcriptional response inhematopoietic stem and progenitor cells (HSPCs), promoting their proliferation and preferential differentiation towards the granulocytic lineage

2019-07-12 | PXD009469 | Pride

Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88 [scRNA-Seq]

Project description:Examination of the single cell trasncriptional profile of bone marrow sorted LSK 10 days post Poly(I:C) challenge

2019-08-12 | GSE112541 | GEO

Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88 [Bulk RNA-Seq]

Project description:examination of the transcriptional profile of LSK and neutrophils (L6G+)

2019-08-12 | GSE112538 | GEO

Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88

Project description:Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88

| PRJNA448157 | ENA

Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88 [scRNA-Seq]

Project description:Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88 [scRNA-Seq]

| PRJNA448160 | ENA

Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88 [Bulk RNA-Seq]

Project description:Spop restrains inflammation-induced emergency hematopoiesis by targeting MyD88 [Bulk RNA-Seq]

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SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association.

Project description:Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD88-associated protein. SPOP was recruited to MyD88 following TLR4 activation. TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm. SPOP depletion promoted the aggregation of MyD88 and recruitment of the downstream signaling kinases IRAK4, IRAK1 and IRAK2. Consistently, overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines, whereas SPOP depletion had the opposite effects. Furthermore, knockdown of SPOP increased MyD88 aggregation and inflammatory cytokine production upon TLR2, TLR7 and TLR9 activation. Our findings reveal a mechanism by which MyD88 is regulated and highlight a role for SPOP in limiting inflammatory responses.

| S-EPMC8245473 | biostudies-literature

The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation.

Project description:The response to systemic infection and injury requires the rapid adaptation of hematopoietic stem cells (HSCs), which proliferate and divert their differentiation toward the myeloid lineage. Significant interest has emerged in understanding the signals that trigger the emergency hematopoietic program. However, the mechanisms that halt this response of HSCs, which is critical to restore homeostasis, remain unknown. Here we reveal that the E3 ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) restrains the inflammatory activation of HSCs. In the absence of Spop, systemic inflammation proceeded in an unresolved manner, and the sustained response in the HSCs resulted in a lethal phenotype reminiscent of hyper-inflammatory syndrome or sepsis. Our proteomic studies decipher that SPOP restricted inflammation by ubiquitinating the innate signal transducer myeloid differentiation primary response protein 88 (MYD88). These findings unearth an HSC-intrinsic post-translational mechanism that is essential for reestablishing homeostasis after emergency hematopoiesis.

| S-EPMC7376385 | biostudies-literature

Trauma Induces Emergency Hematopoiesis through IL-1/MyD88-Dependent Production of G-CSF.

Project description:The inflammatory response to infection or injury dramatically increases the hematopoietic demand on the bone marrow to replace effector leukocytes consumed in the inflammatory response. In the setting of infection, pathogen-associated molecular patterns induce emergency hematopoiesis, activating hematopoietic stem and progenitor cells to proliferate and produce progeny for accelerated myelopoiesis. Sterile tissue injury due to trauma also increases leukocyte demand; however, the effect of sterile tissue injury on hematopoiesis is not well described. We find that tissue injury alone induces emergency hematopoiesis in mice subjected to polytrauma. This process is driven by IL-1/MyD88-dependent production of G-CSF. G-CSF induces the expansion of hematopoietic progenitors, including hematopoietic stem cells and multipotent progenitors, and increases the frequency of myeloid-skewed progenitors. To our knowledge, these data provide the first comprehensive description of injury-induced emergency hematopoiesis and identify an IL-1/MyD88/G-CSF-dependent pathway as the key regulator of emergency hematopoiesis after injury.

| S-EPMC6504560 | biostudies-literature

Obesity-induced inflammation exacerbates clonal hematopoiesis.

Project description:Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity.

| S-EPMC10231999 | biostudies-literature

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