CXCL14 antagonizes the CXCL12-CXCR4 signaling axis

AbstractCXCL12 and CXCL14 are evolutionarily conserved members of the CXC-type chemokine family. CXCL12 binds specifically to the G-protein-coupled receptor CXCR4 to induce the migration of primordial germ cells, hematopoietic stem cells, and inflammation-associated immune cells. In addition, CXCL12-CXCR4 signaling is often enhanced in malignant tumor cells and facilitates increased proliferation as well as metastasis. Although macrophage migration inhibitory factor and extracellular ubiquitin interact with CXCR4 as agonistic factors, CXCL12 was believed to be the sole chemokine ligand for CXCR4. However, a very recent report revealed that CXCL14 binds to CXCR4 with high affinity and efficiently inhibits CXCL12-mediated chemotaxis of hematopoietic progenitor and leukemia-derived cells. CXCL14 does not directly cross-compete with CXCL12 for the CXCR4 binding but instead inactivates CXCR4 via receptor internalization. Because both CXCL12 and CXCL14 are expressed during embryogenesis and brain development in mice, these two chemokines could function in an interactive fashion. We propose that the CXCL14 gene has been conserved from fish to man due to its role in fine-tuning the strength of CXCL12-mediated signal transduction. In addition to its biological implications, the above finding will be important for designing anti-cancer compounds targeting the CXCL12-CXCR4 signaling axis. In fact, a stabilized dimeric peptide containing the C-terminal 51–77 amino acid residues of CXCL14 has been shown to have stronger CXCL12 antagonistic activity than full-length CXCL14.

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CXCR4 signaling at the ovine fetal–maternal interface regulates vascularization, CD34+ cell presence, and autophagy in the endometrium†

Biology of Reproduction ◽

10.1093/biolre/ioz073 ◽

2019 ◽

Vol 101 (1) ◽

pp. 102-111 ◽

Cited By ~ 1

Author(s):

Cheyenne L Runyan ◽

Stacia Z McIntosh ◽

Marlie M Maestas ◽

Kelsey E Quinn ◽

Ben P Boren ◽

...

Keyword(s):

Cross Sections ◽

Angiogenic Factors ◽

Placental Development ◽

Cxcr4 Antagonist ◽

Cxcr4 Signaling ◽

Cellular Autophagy ◽

Signaling Axis ◽

Chemokine Ligand ◽

Clinical Consequences ◽

Ovine Fetal

Abstract Placenta development is characterized by extensive angiogenesis and vascularization but if these processes are compromised placental dysfunction occurs, which is the underlying cause of pregnancy complications such as preeclampsia and intrauterine growth restriction. Dysregulation of placental angiogenesis has emerged as one of the main pathophysiological features in the development of placental insufficiency and its clinical consequences. The signaling axis initiated by chemokine ligand 12 (CXCL12) and its receptor CXCR4 stimulates angiogenesis in other tissues, and may be central to placental vascularization. We hypothesized that CXCL12-CXCR4 signaling governs the pro-angiogenic placental microenvironment by coordinating production of central angiogenic factors and receptors and regulates endometrial cell survival essential for placental function and subsequent fetal longevity. The CXCR4 antagonist, AMD3100, was used to elucidate the role of CXCL12-CXCR4 signaling regarding uteroplacental vascular remodeling at the fetal–maternal interface. On day 12 postbreeding, osmotic pumps were surgically installed and delivered either AMD3100 or PBS into the uterine lumen ipsilateral to the corpus luteum. On day 20, endometrial tissues were collected, snap-frozen in liquid nitrogen, and uterine horn cross sections preserved for immunofluorescent analysis. In endometrium from ewes receiving AMD3100 infusion, the abundance of select angiogenic factors was diminished, while presence of CD34+ cells increased compared to control ewes. Ewes receiving AMD3100 infusion also exhibited less activation of Akt/mTOR signaling, and elevated LC3B-II, a marker of cellular autophagy in endometrium. This study suggests that CXCL12-CXCR4 signaling governs placental homeostasis by serving as a critical upstream mediator of vascularization and cell viability, thereby ensuring appropriate placental development.

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CXCR4 signaling at the fetal–maternal interface may drive inflammation and syncytia formation during ovine pregnancy†

Biology of Reproduction ◽

10.1093/biolre/ioaa203 ◽

2020 ◽

Author(s):

Stacia Z McIntosh ◽

Marlie M Maestas ◽

Jordyn R Dobson ◽

Kelsey E Quinn ◽

Cheyenne L Runyan ◽

...

Keyword(s):

Intracellular Signaling ◽

Placental Development ◽

Cxcr4 Signaling ◽

Proinflammatory Mediators ◽

Placental Angiogenesis ◽

Precise Understanding ◽

Chemokine Ligand ◽

Syncytia Formation ◽

Complex Signaling ◽

Surface Remodeling

Abstract Early pregnancy features complex signaling between fetal trophoblast cells and maternal endometrium directing major peri-implantation events including localized inflammation and remodeling to establish proper placental development. Proinflammatory mediators are important for conceptus attachment, but a more precise understanding of molecular pathways regulating this process is needed to understand how the endometrium becomes receptive to implantation. Both chemokine ligand 12 (CXCL12) and its receptor CXCR4 are expressed by fetal and maternal tissues. We identified this pair as a critical driver of placental angiogenesis, but their additional importance to inflammation and trophoblast cell survival, proliferation, and invasion imply a role in syncytia formation at the fetal–maternal microenvironment. We hypothesized that CXCL12 encourages both endometrial inflammation and conceptus attachment during implantation. We employed separate ovine studies to (1) characterize endometrial inflammation during early gestation in the ewe, and (2) establish functional implications of CXCL12 at the fetal–maternal interface through targeted intrauterine infusion of the CXCR4 inhibitor AMD3100. Endometrial tissues were evaluated for inflammatory mediators, intracellular signaling events, endometrial modifications, and trophoblast syncytialization using western blotting and immunohistochemistry. Endometrial tissue from ewes receiving CXCR4 inhibitor demonstrated dysregulated inflammation and reduced AKT and NFKB, paired with elevated autophagic activity compared to control. Immunohistochemical observation revealed an impairment in endometrial surface remodeling and diminished trophoblast syncytialization following localized CXCR4 inhibition. These data suggest CXCL12–CXCR4 regulates endometrial inflammation and remodeling for embryonic implantation, and provide insight regarding mechanisms that, when dysregulated, lead to pregnancy pathologies such as intrauterine growth restriction and preeclampsia.

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CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice

Blood ◽

10.1182/blood-2010-04-277897 ◽

2011 ◽

Vol 117 (2) ◽

pp. 451-458 ◽

Cited By ~ 58

Author(s):

Mamiko Noda ◽

Yoshiki Omatsu ◽

Tatsuki Sugiyama ◽

Shinya Oishi ◽

Nobutaka Fujii ◽

...

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Nk Cell ◽

Cell Development ◽

Hematopoietic Stem ◽

Adult Mice ◽

Multipotent Progenitors ◽

Chemokine Signaling ◽

Chemokine Ligand

Abstract Natural killer (NK) cells are granular lymphocytes that are generated from hematopoietic stem cells and play vital roles in the innate immune response against tumors and viral infection. Generation of NK cells is known to require several cytokines, including interleukin-15 (IL-15) and Fms-like tyrosine kinase 3 ligand, but not IL-2 or IL-7. Here we investigated the in vivo role of CXC chemokine ligand-12 (CXCL12) and its primary receptor CXCR4 in NK-cell development. The numbers of NK cells appeared normal in embryos lacking CXCL12 or CXCR4; however, the numbers of functional NK cells were severely reduced in the bone marrow, spleen, and peripheral blood from adult CXCR4 conditionally deficient mice compared with control animals, probably resulting from cell-intrinsic CXCR4 deficiency. In culture, CXCL12 enhanced the generation of NK cells from lymphoid-primed multipotent progenitors and immature NK cells. In the bone marrow, expression of IL-15 mRNA was considerably higher in CXCL12-abundant reticular (CAR) cells than in other marrow cells, and most NK cells were in contact with the processes of CAR cells. Thus, CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adults, and CAR cells might function as a niche for NK cells in bone marrow.

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Autoimmune Responses in Oncology: Causes and Significance

International Journal of Molecular Sciences ◽

10.3390/ijms22158030 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8030

Author(s):

Halin Bareke ◽

Pablo Juanes-Velasco ◽

Alicia Landeira-Viñuela ◽

Angela-Patricia Hernandez ◽

Juan Jesús Cruz ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Protein Microarrays ◽

Cross Reactivity ◽

Fine Tuning ◽

Cancer Treatments ◽

Aberrant Expression ◽

Specificity And Sensitivity ◽

Anti Cancer ◽

Life Threatening ◽

Considerable Impact

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

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Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity

Cell Stem Cell ◽

10.1016/j.stem.2021.10.002 ◽

2021 ◽

Author(s):

Katharina Schönberger ◽

Nadine Obier ◽

Mari Carmen Romero-Mulero ◽

Pierre Cauchy ◽

Julian Mess ◽

...

Keyword(s):

Stem Cell ◽

Retinoic Acid ◽

Hematopoietic Stem Cell ◽

Retinoic Acid Signaling ◽

Cell Identity ◽

Hematopoietic Stem ◽

Omics Analysis ◽

Signaling Axis

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CXCR4-SDF-1 Signaling in Nestin+ Mesenchymal Stem Cell Is Required for HSC Maintenance during Homeostasis and Regeneration after Irradiation

Blood ◽

10.1182/blood.v128.22.3883.3883 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3883-3883 ◽

Cited By ~ 1

Author(s):

Pratibha Singh ◽

Louis M. Pelus

Keyword(s):

Stem Cells ◽

Stromal Cell ◽

Cxcr4 Expression ◽

Wild Type ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Cxcr4 Signaling ◽

Hematopoietic Recovery ◽

Hematopoietic Reconstitution

Hematopoietic stem cells (HSC) reside in a complex microenvironment (niche) within the bone marrow (BM), where multiple populations of microenvironmental stromal cells regulate and finely tune their proliferation, differentiation and trafficking. Recent studies have shown that mesenchymal stem cells (MSC) are an essential component of the HSC niche. Intrinsic HSC CXCR4-SDF-1 signaling has been implicated in self-renewal and quiescence; however, the role of microenvironment CXCR4-SDF-1 signaling in supporting HSC function remains unclear. We previously demonstrated that microenvironmental stromal cell-derived CXCR4 is important for HSC recovery, as transplantation of wild-type HSC into CXCR4 deficient recipients showed reduced HSC engraftment. In this study, we now show that CXCR4-SDF-1 signaling in nestin+ MSC regulates HSC maintenance under normal homeostatic conditions and promotes hematopoietic regeneration after irradiation. Multivariate flow cytometry analysis of marrow stroma cells revealed that mouse BM MSCs identified as CD45-Ter119-CD31-Nestin+PDGFR+CD51+ express the CXCR4 receptor, which was confirmed by RT-PCR analysis. To investigate the role of MSC CXCR4 signaling in niche maintenance and support of HSC function, we utilized genetic mouse models, in which CXCR4 could be deleted in specific stromal cell types. Selective deletion of CXCR4 from nestin+ MSC in adult tamoxifen inducible nestin-cre CXCR4flox/flox mice resulted in reduced total MSC in BM (Control vs. Deleted: 647±128 vs. 209±51/femur, respectively, n=5, p<0.05), which was associated with a significant reduction in Lineage-Sca-1+c-Kit+ (LSK) cells (Control vs. Deleted: 18,033±439 vs. 4523±358/femur, respectively n=5, p<0.05). Selective CXCR4 deletion in nestin+ MSC also resulted in enhanced LSK cell egress to the peripheral circulation (Control vs. Deleted: 1022±106 vs. 2690±757/ml blood, respectively n=5, p<0.05), with no detectable difference in HSC cell cycle or apoptosis. However, the repopulation ability of HSC obtained from mice where CXCR4 was deleted in nestin+ MSC was reduced by >2 fold. In contrast, deletion of CXCR4 from osteoblasts using osteocalcin cre CXCR4flox/flox mice had no effect on HSC numbers in BM and blood.To investigate the role of nestin+ MSC CXCR4 signaling in BM niche reconstruction and hematopoietic recovery, we transplanted BM cells from wild-type mice into syngeneic wild-type or nestin+ MSC CXCR4 deleted recipients after lethal irradiation (950 rad) and analyzed HSC homing, niche recovery and hematopoietic reconstitution. Deletion of CXCR4 from nestin expressing MSC resulted in significantly reduced LSK cell homing at 16 hrs post transplantation (Control vs. Deleted: 8643±1371 vs. 3004±1044/ mouse, respectively, n=5, p<0.05). Robust apoptosis and senescence after total body irradiation was observed in nestin expressing MSCs lacking CXCR4 expression. At 15 days post-transplantation, chimeric mice with nestin+ MSC lacking CXCR4 expression displayed attenuated niche recovery and hematopoietic reconstitution compared to mice with wild-type stroma. In conclusion, our study suggests that CXCR4-SDF-1 signaling in nestin+ MSC is critical for the maintenance and retention of HSC in BM during homeostasis and promotes niche regeneration and hematopoietic recovery after transplantation. Furthermore, our data suggest the modulating CXCR4 signaling in the hematopoietic niche could be beneficial as a means to enhance HSC recovery following clinical hematopoietic transplantation or radiation/chemotherapy injury. Disclosures No relevant conflicts of interest to declare.

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Anti-cancer Effect of Hematopoietic Stem Cell-derived Allogeneic-DC Vaccine in Melanoma Metastasis Model

Immune Network ◽

10.4110/in.2006.6.3.154 ◽

2006 ◽

Vol 6 (3) ◽

pp. 154

Author(s):

Myoung Joo Kim ◽

Hye Jin Shon ◽

Soyoung Baek ◽

Kang Eun Lee ◽

Young-Joon Lee ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Melanoma Metastasis ◽

Hematopoietic Stem ◽

Dc Vaccine ◽

Anti Cancer ◽

Metastasis Model

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Integrative genomic analysis of pediatric T- cell lymphoblastic lymphoma reveals candidates of clinical significance

Blood ◽

10.1182/blood.2020005381 ◽

2020 ◽

Author(s):

Tasneem Khanam ◽

Sarah Sandmann ◽

Jochen Seggewiss ◽

Charlotte Marie Ruether ◽

Martin Zimmermann ◽

...

Keyword(s):

T Cell ◽

Cell Lineage ◽

Genomic Analysis ◽

Risk Groups ◽

Lymphoblastic Lymphoma ◽

Fine Tuning ◽

Cell Cycle Regulators ◽

Genome Wide ◽

Signaling Axis ◽

Functional Consequences

T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. Dismal outcomes (15-30%) in case of T-LBL relapses warrants for establishing risk-based treatment in future. This is a first comprehensive, systematic, integrated genome-wide analysis including relapse cases aimed towards identifying molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as putative driver for T-LBL. Activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitutes the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47±17% in patients with KMT2D mutations compared with 14±3% in KMT2D wildtype. Structural analysis of the mutated domains of KMT2D revealed plausible impact on the structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL including high translational potential. The ongoing trial LBL 2018 (NCT04043494) allows prospective validation and subsequent fine-tuning of the stratification criteria for T-LBL risk groups to improve survival of the pediatric patients.

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