A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection

Naina Gour; Hwan Mee Yong; Aishwarya Magesh; Aishwarya Atakkatan; Felipe Andrade; Stephane Lajoie; Xinzhong Dong

doi:10.1016/j.immuni.2024.01.003

A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection

Immunity. 2024 Feb 13;57(2):333-348.e6. doi: 10.1016/j.immuni.2024.01.003. Epub 2024 Jan 30.

Authors

Naina Gour¹, Hwan Mee Yong², Aishwarya Magesh³, Aishwarya Atakkatan⁴, Felipe Andrade⁵, Stephane Lajoie⁶, Xinzhong Dong⁷

Affiliations

¹ Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
² Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
³ Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁴ Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁵ Division of Rheumatology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Otolaryngology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷ Solomon H. Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: xdong2@jhmi.edu.

PMID: 38295799
PMCID: PMC10940224 (available on 2025-02-13)
DOI: 10.1016/j.immuni.2024.01.003

Abstract

The notion that neutrophils exist as a homogeneous population is being replaced with the knowledge that neutrophils adopt different functional states. Neutrophils can have a pro-inflammatory phenotype or an anti-inflammatory state, but how these states are regulated remains unclear. Here, we demonstrated that the neutrophil-expressed G-protein-coupled receptor (GPCR) Mrgpra1 is a negative regulator of neutrophil bactericidal functions. Mrgpra1-mediated signaling was driven by its ligand, neuropeptide FF (NPFF), which dictated the balance between pro- and anti-inflammatory programming. Specifically, the Mrgpra1-NPFF axis counter-regulated interferon (IFN) γ-mediated neutrophil polarization during acute lung infection by favoring an alternative-like polarization, suggesting that it may act to balance overzealous neutrophilic responses. Distinct, cross-regulated populations of neutrophils were the primary source of NPFF and IFNγ during infection. As a subset of neutrophils at steady state expressed NPFF, these findings could have broad implications in various infectious and inflammatory diseases. Therefore, a neutrophil-intrinsic pathway determines their cellular fate, function, and magnitude of infection.

Keywords: IFNγ; Mrgpra1 GPCR; NPFF; lung infection; neuropeptide FF; neutrophil polarization; neutrophils.

MeSH terms

Anti-Inflammatory Agents
Bacterial Infections*
Humans
Neuropeptides*
Neutrophils / metabolism
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Receptors, Neuropeptide / metabolism

Substances

Receptors, Neuropeptide
Receptors, G-Protein-Coupled
Neuropeptides
Anti-Inflammatory Agents

Abstract

MeSH terms

Substances

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