α1B/D-adrenoceptors regulate chemokine receptor-mediated leukocyte migration via formation of heteromeric receptor complexes

It is known that catecholamines regulate innate immune functions. The underlying mechanisms, however, are not well understood. Here we show that at least 20 members of the human chemokine receptor (CR) family heteromerize with one or more members of the alpha(1)-adrenergic receptor (AR) family in recombinant systems and that such heteromeric complexes are detectable in human monocytes and the monocytic leukemia cell line THP-1. Ligand binding to alpha(1)-ARs inhibited migration toward agonists of the CR heteromerization partners of alpha(1B/D)-ARs with high potency and 50 to 77% efficacy but did not affect migration induced by a noninteracting CR. Incomplete siRNA knockdown of alpha(1B/D)-ARs in THP-1 cells partially inhibited migration toward agonists of their CR heteromerization partners. Complete alpha(1)(B)-AR knockout via CRISPR-Cas9 gene editing in THP-1 cells (THP-1_ADRA1B(KO)) resulted in 82% reduction of alpha(1D)-AR expression and did not affect CR expression. Migration of THP-1_ADRA1B(KO) cells toward agonists of CR heteromerization partners of alpha(1B/D)-ARs was reduced by 82 to 95%. Our findings indicate that CR:alpha(1B/D)-AR heteromers are essential for normal function of CR heteromerization partners, provide a mechanism underlying neuroendocrine control of leukocyte trafficking, and offer opportunities to modulate leukocyte and/or cancer cell trafficking in disease processes.

Automated summary

The study reveals that catecholamines regulate innate immune functions by forming heteromeric complexes with chemokine receptor (CR) and alpha(1)-adrenergic receptor (AR) family members. These heteromers play a crucial role in leukocyte and cancer cell migration and offer potential opportunities for modulating cell trafficking in disease processes.