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

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.

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…The stress‐regulating chemokine‐like cytokine, macrophage migration inhibitory factor (MIF) features danger‐associated molecular pattern–like characteristics and is an important upstream regulator of the innate immune response 18, 19, 20. Although it generally promotes acute and chronic inflammatory processes, MIF has been demonstrated to also exhibit protective effects during myocardial ischemia/reperfusion injury, especially in the ischemic and early reperfusion phase.…”

Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation

“…Previous studies suggested that CXCR4 regulates gene expression and migration in a number of cell types, including leukocytes, hematopoietic progenitor cells, and tumor cells (31,32). In addition, CXCR4 impacts on thymic β-selection in T cells (50).…”

“…We therefore investigated whether GPCRs enriched in Th17 low_path have the potential to modulate the transition into Th17 high_path . One of the receptors negatively correlated with expression of Csf2 and Tnf was Cxcr4 ( Figure 4A), a chemokine receptor that has been suggested to regulate not only cell migration (31,32), but also T cell receptor signaling (33). It is unclear whether CXCR4 is able to modulate the functional state of differentiated Th17 cells.…”

CXCL12 and CXCR4 in the Peripheral Blood of Patients with Parkinson’s Disease

“…Macrophage migration inhibitory factor (MIF) has been recently identified as a ligand for CXCR4. MIF has chemokine-like functions and exerts chemotactic effects through CXCR4 and CXCR2 chemokine receptors [28]. It has the ability to induce neuroinflammation by activation of microglia, which produce proinflammatory cytokines.…”