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

Ahmed M Youssef¹, Dong-Keun Song²

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

Purinergic Signalling

|July 2, 2022

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 A_2B 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, Δψ_m) 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 A_2B 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.

Insights

Lysophosphatidylcholine (LPC) suppresses inflammation by inducing adenosine release from macrophages. This process involves magnesium signaling and counteracts inflammatory responses, promoting tissue repair.

Area of Science:

Immunology
Cell Biology
Biochemistry

Background:

Macrophages play dual roles in tissue integrity, capable of both harm and protection.
Excessive inflammatory mediators released by macrophages can damage tissues.
Understanding regulatory mechanisms of macrophage-mediated inflammation is crucial.

Purpose of the Study:

To investigate the role of lysophosphatidylcholine (LPC) in regulating macrophage inflammatory responses.
To elucidate the signaling pathways involved in LPC-mediated suppression of inflammation.
To determine if LPC induces adenosine release as a brake on macrophage activity.

Main Methods:

Utilized bone marrow-derived macrophages (BMDMs) for experiments.
Investigated signaling pathways including cAMP/PKA, LKB1/AMPK, and calcium signaling.
Employed pharmacological inhibitors (TRPM7 blockade) and antisense treatment.
Assessed adenosine release, magnesium influx, mitochondrial membrane potential, and ATP production.
Measured netrin-1 production and connexin-43 phosphorylation.
Evaluated macrophage chemotaxis and adenosine release under hypoxia and acidosis.

Main Results:

LPC induces adenosine release from macrophages via G2A and A2B receptors, acting as an anti-inflammatory brake.
The process involves PGE2 production, cAMP/PKA activation, LKB1/AMPK pathway, Mg2+ influx, and increased mitochondrial potential and ATP production.
Adenosine is released intracellularly via ENT1, with calcium signaling and PKA cooperating to regulate its efflux.
TRPM7 blockade and antisense treatment inhibited LPC-induced adenosine release and Mg2+ influx.
LPC suppressed LPS-induced phosphorylation of connexin-43, potentially counteracting TLR4-mediated inflammation.
LPC increased netrin-1 production, which signals anti-inflammatory effects via A2B receptor.
LPC enhanced hypoxia- or acidosis-induced adenosine release from BMDMs.

Conclusions:

LPC exerts a brake-like action on macrophages by inducing adenosine release.
Cellular magnesium signaling is integral to LPC-mediated adenosine release and anti-inflammatory effects.
These findings highlight a novel mechanism for terminating inflammation involving LPC and adenosine signaling.

Read full analysis

Keywords:

Adenosine release Bone marrow-derived macrophages Intracellular magnesium Lipopolysaccharide Lysophosphatidylcholine TRPM7

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