Chemokine receptor hetero-oligomers regulate monocyte chemotaxis

Area of Science:

• Molecular Pharmacology
• Immunology
• Cellular Signaling

Background:

• Stress significantly impacts immune cell function, but the molecular mechanisms remain largely unknown.
• Chemokine receptors (CRs) are known to heteromerize with α1-adrenoceptors (α1-ARs), influencing CR regulation.
• Arginine vasopressin receptor 1A (AVPR1A) is implicated in various physiological processes, including stress responses.

Purpose of the Study:

• To investigate the heteromerization of arginine vasopressin receptor 1A (AVPR1A) with various human chemokine receptors (CRs).
• To elucidate the role of AVPR1A:CR heteromers in regulating immune cell chemotaxis.
• To determine how stress hormones, via AVPR1A and α1-ARs, modulate immune cell trafficking through these receptor complexes.

Main Methods:

• Recombinant expression systems to study AVPR1A and CR heteromerization.
• Detection of heteromers in THP-1 cells and primary human monocytes.
• Bioluminescence resonance energy transfer (BRET) to monitor G protein activation.
• CRISPR/Cas9 gene editing to create THP-1 cells lacking AVPR1A or α1B-AR.

Main Results:

• AVPR1A forms heteromers with most human CRs (except CXCR1) in vitro and in immune cells.
• Ligand-free AVPR1A differentially regulates CR-mediated chemotaxis efficacy.
• AVPR1A ligands disrupt AVPR1A:CR heteromers, altering chemotaxis (enhancing CCR1, inhibiting CCR2, CCR8, CXCR4).
• Interdependent hetero-oligomeric complexes of CRs, α1B/D-ARs, and AVPR1A control CR-mediated chemotaxis.

Conclusions:

• AVPR1A plays a significant role in modulating immune cell chemotaxis through heteromerization with CRs.
• Stress hormones can regulate immune cell trafficking by targeting these complex hetero-oligomeric receptor structures.
• These findings reveal a novel molecular mechanism linking stress, receptor complexes, and immune cell function.