# Molecular mechanisms regulating leukocyte trafficking

> **NIH NIH R21** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $186,875

## Abstract

Project Summary/Abstract
The autonomous nervous system regulates innate immune functions during the stress or “fight and flight”
response through the release of endogenous catecholamines, which activate the G protein-coupled receptor
(GPCR) family of adrenergic receptors (ARs) expressed in the immune system. The roles of α1-ARs in the
regulation of innate immune functions, however, are poorly understood and the molecular mechanisms
underlying cross-talk between the neurohormonal and innate immune system remain to be determined. The
family of chemokine receptors (CRs) is essential for the regulation of leukocyte recruitment and plays important
roles in all aspects of inflammation and in numerous disease processes. Recently, we discovered that α1-ARs
form hetero-oligomeric complexes with chemokine (C-X-C motif) receptor (CXCR) 4 and with atypical chemokine
receptor (ACKR) 3, and that α1B-AR within heteromeric CXCR4:α1B-AR complexes regulates CXCR4-mediated
migration of human vascular smooth muscle cells. It is unknown whether heteromeric complexes between CRs
and α1-ARs exist in leukocytes. We observed in pilot experiments that hetero-oligomeric complexes between
α1A/B/D-AR and CXCR4 are detectable on the cell surface of THP-1 cells and in freshly isolated human peripheral
blood mononuclear cells. Furthermore, we performed preliminary intermolecular bioluminescence resonance
energy transfer (BRET) experiments and detected that α1b-AR is able to form heteromeric complexes with
multiple members of the CR family. This leads to our working hypothesis that the formation of hetero-oligomeric
complexes between α1-ARs and CRs is a common molecular mechanism through which the neurohormonal
system interacts with the innate immune system to regulate CR-mediated leukocyte trafficking in health and
disease. To test this hypothesis, we will focus on monocytes as a major cell population in the innate immune
system and on heteromers between CRs and α1B-AR to provide proof-of-concept. We propose the following
specific aims: 1. To study the distribution and function of CR:α1B-AR heteromeric complexes in human
monocytes. We will determine which CRs are able to form heteromers with α1B-AR, define the patterns of
receptor heteromerization and assess the effects of receptor heteromerization on CR signaling and function. 2.
To assess the roles of α1-ARs and of CR:α1B-AR heteromeric complexes in the regulation of monocyte
recruitment during inflammation in vivo. Here we will utilize MacBlue mice in a peritonitis model to evaluate
the roles of α1-ARs and CR:α1B-AR heteromers in the regulation of monocyte migration in inflammation. The
proposed exploratory/developmental studies will provide the scientific basis to establish receptor
heteromerization as a mechanism through which the neurohormonal system controls CR-mediated leukocyte
trafficking. These data could lead to a paradigm shift in the understanding of the regulation of leukocyte
recruitment and are expected to iden...

## Key facts

- **NIH application ID:** 9890986
- **Project number:** 5R21AI139827-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Matthias Majetschak
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,875
- **Award type:** 5
- **Project period:** 2019-03-11 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890986

## Citation

> US National Institutes of Health, RePORTER application 9890986, Molecular mechanisms regulating leukocyte trafficking (5R21AI139827-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9890986. Licensed CC0.

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