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      Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives

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          Abstract

          CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival, and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF) was identified as an alternative, non-cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor 3 (ACKR3) (previously CXCR7) has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and to evoke CXCL12- and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb) and the viral protein gp120 (HIV) have been reported as CXCR4 ligands, whereas viral chemokine vMIP-II (Herpesvirus) and human β3-defensin (HBD-3) have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.

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          This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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            Chemokines: a new classification system and their role in immunity.

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              Macrophage migration inhibitory factor: a regulator of innate immunity

              Key Points Cytokines are essential effector molecules of innate immunity that initiate and coordinate the cellular and humoral responses aimed, for example, at the eradication of microbial pathogens. Discovered in the late 1960s as a product of activated T cells, the cytokine macrophage migration inhibitory factor (MIF) has been discovered recently to carry out important functions as a mediator of the innate immune system. Constitutively expressed by a broad spectrum of cells and tissues, including monocytes and macrophages, MIF is rapidly released after exposure to microbial products and pro-inflammatory mediators, and in response to stress. After it is released, MIF induces pro-inflammatory biological responses that act as a regulator of immune responses. MIF activates the extracellular signal-regulated kinase 1 (ERK1)/ERK2–mitogen-activated protein kinase pathway, inhibits the activity of JUN activation domain-binding protein 1 (JAB1) — a co-activator of the activator protein 1 (AP1) — upregulates the expression of Toll-like receptor 4 to promote the recognition of endotoxin-expressing bacterial pathogens, sustains pro-inflammatory function by inhibiting p53-dependent apoptosis of macrophages and counter-regulates the immunosuppressive effects of glucocorticoids on immune cells. As a pro-inflammatory mediator, MIF has been shown to be implicated in the pathogenesis of severe sepsis and septic shock, acute respiratory distress syndrome, and several other inflammatory and autoimmune diseases, including rheumatoid arthritis, glomerulonephritis and inflammatory bowel diseases. Given its crucial role as a regulator of innate and acquired immunity, pharmacological or immunological modulation of MIF activity might offer new treatment opportunities for the management of acute and chronic inflammatory diseases.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                21 August 2015
                2015
                : 6
                : 429
                Affiliations
                [1] 1Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University , Aachen, Germany
                [2] 2Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University , Aachen, Germany
                [3] 3Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich , Munich, Germany
                [4] 4DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance , Munich, Germany
                [5] 5Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , Maastricht, Netherlands
                [6] 6August-Lenz-Stiftung, Institute for Cardiovascular Research, Ludwig-Maximilians-University Munich , Munich, Germany
                Author notes

                Edited by: Mariagrazia Uguccioni, Institute for Research in Biomedicine, Switzerland

                Reviewed by: Paul Proost, KU Leuven, Belgium; Toshihiro Ito, Nara Medical University, Japan

                *Correspondence: Jürgen Bernhagen, Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstrasse 30, Aachen D-52074, Germany, jbernhagen@ 123456ukaachen.de ; Heidi Noels, Institute of Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstrasse 30, Aachen D-52074, Germany, hnoels@ 123456ukaachen.de

                Lukas Pawig and Christina Klasen share first authorship.

                Jürgen Bernhagen and Heidi Noels share last authorship.

                Specialty section: This article was submitted to Chemoattractants, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00429
                4543903
                26347749
                f374db72-54ce-4c8d-8c11-f42d94a197f7
                Copyright © 2015 Pawig, Klasen, Weber, Bernhagen and Noels.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 June 2015
                : 07 August 2015
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 250, Pages: 23, Words: 21670
                Funding
                Funded by: Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University
                Funded by: START Program and the Habilitation Program of the Medical School of the RWTH Aachen University
                Funded by: Deutsche Herzstiftung 10.13039/501100005971
                Award ID: F/40/12
                Funded by: Deutsche Stiftung für Herzforschung 10.13039/501100005970
                Award ID: F/40/12
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Funded by: German Centre for Cardiovascular Research
                Funded by: European Research Council 10.13039/501100000781
                Funded by: Bundesministerium für Bildung und Forschung 10.13039/501100002347
                Funded by: Fondation Leducq 10.13039/501100001674
                Categories
                Immunology
                Review

                Immunology
                chemokine,signaling,cxcr4,cxcl12,mif,cxcr7,ackr3,ubiquitin
                Immunology
                chemokine, signaling, cxcr4, cxcl12, mif, cxcr7, ackr3, ubiquitin

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