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RETRACTED ARTICLE: Lysophosphatidylcholine induces adenosine release from macrophages via TRPM7-mediated mitochondrial activation

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This article was retracted on 12 August 2023

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Abstract

Even though macrophages have the potential to harm tissues through excessive release of inflammatory mediators, they play protective roles to maintain tissue integrity. In this study, we hypothesized that lysophosphatidylcholine (LPC), via G2A and A2B receptors, puts brakes on macrophages by the induction of adenosine release which could contribute to termination of inflammation. Mechanistically, LPC-induced PGE2 production followed by the activation of cAMP/protein kinase A (PKA) pathway which results in the activation of LKB1/AMPK signaling pathway leading to increasing Mg2+ influx concomitantly with an increase in mitochondrial membrane potential (MMP, Δψm) and ATP production. Then, ATP is converted to adenosine intracellularly followed by efflux via ENT1. In a parallel pathway, LPC-induced elevation of cytosolic calcium was essential for adenosine release, and Ca2+/calmodulin signaling cooperated with PKA to regulate ENT1 permeation to adenosine. Pharmacological blockade of TRPM7 and antisense treatment suppressed LPC-induced adenosine release and magnesium influx in bone marrow-derived macrophages (BMDMs). Moreover, LPC suppressed LPS-induced phosphorylation of connexin-43, which may counteract TLR4-mediated inflammatory response. Intriguingly, we found LPC increased netrin-1 production from BMDMs. Netrin-1 induces anti-inflammatory signaling via A2B receptor. In the presence of adenosine deaminase which removes adenosine in the medium, the chemotaxis of macrophages toward LPC was significantly increased. Hypoxia and metabolic acidosis are usually developed in a variety of inflammatory situations such as sepsis. We found LPC augmented hypoxia- or acidosis-induced adenosine release from BMDMs. These results provide evidence of LPC-induced brake-like action on macrophages by adenosine release via cellular magnesium signaling.

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Abbreviations

AMPK:

AMP-activated protein kinase

APCP:

Adenosine 5′-(α,β-methylene)diphosphate

BMDMs:

Bone marrow-derived macrophages

BAPTA-AM:

1,2-Bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid

CaMKII:

Calcium/calmodulin-dependent kinase kinase 2

ENT1:

Equilibrative nucleoside transporter

HIF-1α:

Hypoxia-inducible factor 1α

LPC:

Lysophosphatidylcholine

LPS:

Lipopolysaccharide

LKB1:

Liver kinase B1

MMP:

Mitochondrial membrane potential

NBTI:

S-(4-nitrobenzyl)-6-thioinosine

TRPM7:

Transient receptor potential melastatin member 7

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Acknowledgements

We thank Shin-Hae Kang for helping AMY with the experiments.

Funding

This research was supported by the basic research program of the National Research Foundation of Korea (NRF), funded by the Ministry of Science ICT (NRF-2020R1F1A1067708).

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea

    Ahmed M. Youssef & Dong-Keun Song

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  1. Ahmed M. Youssef
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  2. Dong-Keun Song
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Contributions

DKS conceived, DKS and AMY designed this study. AMY did the experiments. AMY and DKS analyzed the data and wrote the manuscript.

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Correspondence to Dong-Keun Song.

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Youssef, A.M., Song, DK. RETRACTED ARTICLE: Lysophosphatidylcholine induces adenosine release from macrophages via TRPM7-mediated mitochondrial activation. Purinergic Signalling 18, 317–343 (2022). https://doi.org/10.1007/s11302-022-09878-y

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