Chemokine receptor hetero-oligomers regulate monocyte chemotaxis

It is known that stress in fluences immune cell function. The underlying molecular mechanisms are unclear. We recently reported that many chemokine receptors (CRs) heteromerize with alpha 1 -adrenoceptors ( alpha 1 -ARs) through which CRs are regulated. Here, we show that arginine vasopressin receptor 1A (AVPR1A) heteromerizes with all human CRs, except chemokine (C -X -C motif) receptor (CXCR)1, in recombinant systems and that such heteromers are detectable in THP-1 cells and human monocytes. We demonstrate that ligand-free AVPR1A differentially regulates the ef ficacy of CR partners to mediate chemotaxis and that AVPR1A ligands disrupt AVPR1A:CR heteromers, which enhances chemokine (C -C motif) receptor (CCR)1-mediated chemotaxis and inhibits CCR2-, CCR8-, and CXCR4-mediated chemotaxis. Using bioluminescence resonance energy transfer to monitor G protein activation and CRISPR/Cas9 gene-edited THP-1 cells lacking AVPR1A or alpha 1B -AR, we show that CRs that share the propensity to heteromerize with alpha 1B/D - ARs and AVPR1A exist and function within interdependent hetero-oligomeric complexes through which the ef ficacy of CRs to mediate chemotaxis is controlled. Our findings suggest that hetero-oligomers composed of CRs, alpha 1B/D -ARs, and AVPR1A may enable stress hormones to regulate immune cell traf ficking.