Abstract
Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed after 24 h of stimulation by endotoxin. MR-39 was the only FPR2 ligand that attenuated LPS-evoked changes in the mitochondrial membrane potential and diminished the ROS and NO release. Moreover, the LPS-induced alterations in the microglial phenotype were modulated by LXA4, AT-LXA4, and MR-39. The anti-inflammatory effect of MR-39 on the IL-1β release was mediated through FPR2. All tested ligands inhibited TNF-α production, while AT-LXA4 and MR-39 also diminished IL-6 levels in LPS-stimulated microglia. The favorable action of LXA4 and MR-39 was mediated through the inhibition of ERK1/2 phosphorylation. AT-LXA4 and MR39 diminished the phosphorylation of the transcription factor NF-κB, while AT-LXA4 also affected p38 kinase phosphorylation. Our results suggest that new pro-resolving synthetic mediators can represent an attractive treatment option for the enhancement of RoI, and that FPR2 can provide a perspective as a target in immune-related brain disorders.
Highlights
A large body of evidence has demonstrated that microglia manage innate and adaptive immune responses in various pathological and regenerative processes in the central nervous system (CNS) [1,2]
In the first part of the experiments, we evaluated the time-dependent properties of lipoxin A4 (LXA4), aspirin-triggered lipoxin A4 (AT-LXA4), and MR-39 against LPSinduced lactate dehydrogenase (LDH) release, which is a marker of cell death after damage to the plasma membrane
The present findings show that LXA4, AT-LXA4, and MR-39 exhibit time-dependent protective and anti-inflammatory effects in LPS-stimulated microglia
Summary
A large body of evidence has demonstrated that microglia manage innate and adaptive immune responses in various pathological and regenerative processes in the central nervous system (CNS) [1,2]. It is believed that active microglia can clear cellular debris by phagocytosis, thereby promoting tissue repair and regulating the response to pathogens. On the other hand, prolonged or excessive activation leads to the functional changes and switch of microglia from regulatory to inflammatory/neurotoxic functions [3,4,5], which allows us to infer that microglia are highly sensitive indicators of the brain condition [6,7]. In response to immune stimulation, microglia upregulate a number of pro-inflammatory surface proteins (e.g., CD40 and MHC II), cytokines (IL-18, IL-1β, TNF-α, and IL-6), and neurotoxic mediators, such as nitric oxide (NO), prostaglandin (PG), and reactive oxygen species (ROS) [14]. The anti-inflammatory response leads to the expression of various markers (e.g., Arg-1 and CD206) and mediators (e.g., insulin growth factor 1 (IGF-1) and/or IL-10) and is involved in the limitation of inflammation and the restoration of homeostasis [13,15,16]
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