Beta-Chemokine CCL15 Affects the Adhesion and Migration of Hematopoietic Progenitor Cells

Richter, Rudolf; Rüster, Brigitte; Bistrian, Roxana; Forssmann, Wolf‐Georg; Seifried, Erhard; Henschler, Reinhard

doi:10.1159/000370168

Cited by 6 publications

(4 citation statements)

References 57 publications

(61 reference statements)

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“…Our results suggest that US28 ligand binding and signaling act to fine-tune HPC cellular differentiation toward a phenotype that promotes the capacity of the virus to reactivate, namely, toward a myeloid lineage, while also maintaining some degree of stemness. It is worth mentioning that other chemokines (CCL3, CCL15, and CXCL12) play important roles in hematopoiesis and myeloid cell differentiation (49–51). While it is unclear precisely why US28 ligand binding activity (and signaling) is required to maintain latency, US28 signals through multiple pathways that influence cellular differentiation, including NF-κB, Src, FAK, Pyk2, RhoA, and Wnt.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 ⁺ Hematopoietic Progenitor Cells and Humanized NSG Mice

Crawford

Caposio

Kreklywich

et al. 2019

mBio

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Human cytomegalovirus (HCMV) infection of CD34+hematopoietic progenitor cells (CD34+HPCs) provides a critical reservoir of virus in stem cell transplant patients, and viral reactivation remains a significant cause of morbidity and mortality. The HCMV chemokine receptor US28 is implicated in the regulation of viral latency and reactivation. To explore the role of US28 signaling in latency and reactivation, we analyzed protein tyrosine kinase signaling in CD34+HPCs expressing US28. US28-ligand signaling in CD34+HPCs induced changes in key regulators of cellular activation and differentiation.In vitrolatency and reactivation assays utilizing CD34+HPCs indicated that US28 was required for viral reactivation but not latency establishment or maintenance. Similarly, humanized NSG mice (huNSG) infected with TB40E-GFP-US28stop failed to reactivate upon treatment with granulocyte-colony-stimulating factor, but viral genome levels were maintained. Interestingly, HCMV-mediated changes in hematopoiesis during latencyin vivoandin vitrowas also dependent upon US28, as US28 directly promoted differentiation toward the myeloid lineage. To determine whether US28 constitutive activity and/or ligand-binding activity were required for latency and reactivation, we infected both huNSG mice and CD34+HPCsin vitrowith HCMV TB40E-GFP containing the US28-R129A mutation (no CA) or Y16F mutation (no ligand binding). TB40E-GFP-US28-R129A was maintained during latency and exhibited normal reactivation kinetics. In contrast, TB40E-GFP-US28-Y16F exhibited high levels of viral genome during latency and reactivation, indicating that the virus did not establish latency. These data indicate that US28 is necessary for viral reactivation and ligand binding activity is required for viral latency, highlighting the complex role of US28 during HCMV latency and reactivation.IMPORTANCEHuman cytomegalovirus (HCMV) can establish latency following infection of CD34+hematopoietic progenitor cells (HPCs), and reactivation from latency is a significant cause of viral disease and accelerated graft failure in bone marrow and solid-organ transplant patients. The precise molecular mechanisms of HCMV infection in HPCs are not well defined; however, select viral gene products are known to regulate aspects of latency and reactivation. The HCMV-encoded chemokine receptor US28, which binds multiple CC chemokines as well as CX3CR1, is expressed both during latent and lytic phases of the virus life cycle and plays a role in latency and reactivation. However, the specific timing of US28 expression and the role of ligand binding in these processes are not well defined. In this report, we determined that US28 is required for reactivation but not for maintaining latency. However, when present during latency, US28 ligand binding activity is critical to maintaining the virus in a quiescent state. We attribute the regulation of both latency and reactivation to the role of US28 in promoting myeloid lineage cell differentiation. These data highlight the dynamic and multifunctional nature of US28 during HCMV latency and reactivation.

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 ⁺ Hematopoietic Progenitor Cells and Humanized NSG Mice

Crawford

Caposio

Kreklywich

et al. 2019

mBio

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“…Levels of CXCL1/Groα, a chemokine ligand for CXCR2, which promotes neutrophil egress from bone marrow (25), were in the normal range for WHIM patients with a wide range of values but were repeatedly undetectable in WHIM-09 (and in 50% of healthy donors). Strikingly, serum levels of CCL15/MIP-1δ, which regulates hematopoietic progenitor cell retention and adhesion in bone marrow as well as HSC repopulation activity (26), were increased by 400% for WHIM-09 compared to both healthy donors and WHIM patients. We do not know the source of CCL15 in the patient.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, although her serum levels of myeloid growth factors were also normal, WHIM-09 had extremely high levels of CCL15, a chemokine known to induce hematopoietic progenitor cell migration and adhesion to vascular cell adhesion molecule-1 (VCAM-1), as well as to negatively regulate colony size in CFU assays using mouse Lin − Sca1 + HPCs in vitro. CCL15 also markedly enhances repopulation ability of bone marrow cells in competitive engraftment assays in vivo (26). Increased serum CCL15 levels have also been reported in patients undergoing HPC mobilization (26).…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis

Liu

Yang

et al. 2017

J Clin Immunol

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WHIM-09 is the first patient described with WHIM syndrome, an autosomal dominant form of neutropenia related to bone marrow retention of neutrophils. Originally diagnosed incorrectly with autoimmune neutropenia, the patient underwent splenectomy at age 9, but the absolute neutrophil count (ANC) did not rise. Subsequently, she was spontaneously cured by chromothripsis (chromosome shattering), which deleted the disease allele CXCR4 , and 163 other genes, on chromosome 2 in a single hematopoietic stem cell (HSC). Chromothriptic CXCR4 HSCs replaced CXCR4 WHIM HSCs, and the ANC rose to a new sustained and benign baseline ~ 2-3-fold above normal that had remained unexplained. Here, we show that splenectomized Cxcr4 mice had sustained and benign neutrophilia, phenocopying neutrophilia in WHIM-09. In addition, WHIM-09's granulocyte-macrophage precursor cells possessed increased granulocyte colony-forming activity ex vivo. Thus, WHIM-09's neutrophilia may be multifactorial, involving neutrophil-extrinsic factors (splenectomy), as well as CXCR4 haploinsufficiency-dependent neutrophil-intrinsic factors (increased myeloid precursor cell differentiation). The strong bone marrow retention signal for neutrophils conferred by the WHIM mutation may have prevented neutrophilia after splenectomy until the mutation was deleted by chromothripsis.

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Chemokine CCL15

Richter

Gupta

Forssmann

2016

Encyclopedia of Inflammatory Diseases

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Beta-Chemokine CCL15 Affects the Adhesion and Migration of Hematopoietic Progenitor Cells

Cited by 6 publications

References 57 publications

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 ⁺ Hematopoietic Progenitor Cells and Humanized NSG Mice

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 ⁺ Hematopoietic Progenitor Cells and Humanized NSG Mice

Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis

Chemokine CCL15

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Beta-Chemokine CCL15 Affects the Adhesion and Migration of Hematopoietic Progenitor Cells

Cited by 6 publications

References 57 publications

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 + Hematopoietic Progenitor Cells and Humanized NSG Mice

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 + Hematopoietic Progenitor Cells and Humanized NSG Mice

Mechanisms of Sustained Neutrophilia in Patient WHIM-09, Cured of WHIM Syndrome by Chromothripsis

Chemokine CCL15

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Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 ⁺ Hematopoietic Progenitor Cells and Humanized NSG Mice

Human Cytomegalovirus US28 Ligand Binding Activity Is Required for Latency in CD34 ⁺ Hematopoietic Progenitor Cells and Humanized NSG Mice