The Role of the CXCL12/CXCR4/ACKR3 Axis in Autoimmune Diseases

Abstract

Chemokine receptors are members of the G protein-coupled receptor superfamily. These receptors are intimately involved in cell movement, and thus play a critical role in several physiological and pathological situations that require the precise regulation of cell positioning. CXCR4 is one of the most studied chemokine receptors and is involved in many functions beyond leukocyte recruitment. During embryogenesis, it plays essential roles in vascular development, hematopoiesis, cardiogenesis, and nervous system organization. It has been also implicated in tumor progression and autoimmune diseases and, together with CD4, is one of the co-receptors used by the HIV-1 virus to infect immune cells. In contrast to other chemokine receptors that are characterized by ligand promiscuity, CXCR4 has a unique ligand-stromal cell-derived factor-1 (SDF1, CXCL12). However, this ligand also binds ACKR3, an atypical chemokine receptor that modulates CXCR4 functions and is overexpressed in multiple cancer types. The CXCL12/CXCR4/ACKR3 axis constitutes a potential therapeutic target for a wide variety of inflammatory diseases, not only by interfering with cell migration but also by modulating immune responses. Thus far, only one antagonist directed against the ligand-binding site of CXCR4, AMD3100, has demonstrated clinical relevance. Here, we review the role of this ligand and its receptors in different autoimmune diseases.

Keywords: ACKR3; CXCL12 chemokine; CXCR4 = chemokine receptor 4; autoimmunity; chemokines/chemokine receptors; inflammation.

Figure 1

Structure of CXCR4. Models created using the Swiss-Model web server (119), with PDB 3oe8 as a reference for CXCR4 and PDB 1a15 for CXCL12, which was superposed to vMIP-II present in PDB 4 rws to build a CXCR4:CXCL12 complex. (A) Ribbon representation of a CXCR4 monomer in complex with a surface representation of CXCL12. Residues implicated in CXCL12 signal transmission are depicted as colored spheres corresponding to the specific state of signal transference showed by the pink arrowhead indicating the direction of the CXCR4:CXCL12 axis signal transit. Blue colored residues are part of the CXCL12 binding site that contact the green colored residues responsible for the initiation of the signal transmission toward the cytoplasm. Subsequent signal propagation through a hydrophobic bridge, in orange, allows conformational changes in TMVII inducing translation of specific residues (red spheres), depicted by an arrow, that will act like a microswitch and position the G-protein binding residues (pink) in an active conformation. [Adapted from Wescott et. al. (51)]. (B) Cartoon representation of the CXCR4 dimer. Residues contacting between monomers are shown by pink spheres for CXCR4:IT1t complex, cyan for CXCR4:CVX15 complex and orange for oligomerization inhibition after mutating residues 239–246 in TMVI (21).