MSC administration resolves experimental acute gout increasing specialized pro-resolving mediators synthesis through
Ismael Bermejo-Álvarez1, Cristina Vázquez1, Alberto Irigaray-Moreno1
1Joint and Bone Research Unit, Rheumatology Department, IIS-Fundación Jiménez Díaz UAM, Reyes Católicos 2, 28040, Madrid, Spain.
Background:
The resolution of inflammation is an active process triggered in the acute phase of inflammation and mainly directed by specialized pro-resolving mediators (SPMs). Modulating the inflammatory response in favor of resolution is a therapeutic strategy of enormous interest and value. Previous studies have shown that human adipose mesenchymal stem cells (MSCs) possess the ability to shorten the acute inflammatory response by hinting an early cyclooxygenase (COX)-2 induction. We studied the potential of MSC to accelerate the resolution of inflammation through the direct promotion of the local synthesis of SPMs, and the role of prostaglandin (PG) E2 release in this process in a model of experimental acute arthritis.
Methods:
Gouty arthritis was induced in male New Zealand rabbits via intra-articular injection of monosodium urate (MSU) crystals. Human adipose-derived MSCs were administered systemically in a single dose. Synovial membrane levels of SPMs were measured by liquid chromatography-tandem mass spectrometry, PGE2 and genes related to the pro-resolving and anti-inflammatory pathways were assessed. Employing THP-1-derived macrophages and human adipose-derived MSC co-cultures stimulated with MSU crystals, we elucidated the mechanisms associated to the induction of resolution by MSCs.
Results:
MSC treatment enhanced the local release of a broad range of SPM precursors and active mediators in the synovial membrane of rabbits with gouty arthritis. This release occurred simultaneously with an early increase in PGE₂ levels, and an upregulation of COX-2 and the PGE2 receptor EP4. Additionally, an early anti-inflammatory gene response was observed, characterized by increased expression of IL-10, indoleamine 2,3-dioxygenase-1 (IDO-1), and Formyl Peptide Receptor2 (FPR2). In cell culture experiments, we confirmed that MSCs are responsible for the release of pro-resolving and anti-inflammatory mediators, promoting macrophage efferocytosis and polarization towards a pro-resolving and anti-inflammatory M2 phenotype in a COX-2- and FPR2-dependent manner.
Conclusions:
MSCs exerted a pro-resolving effect on the synovial membrane in gouty arthritis. This therapeutic action may be driven by an early superinduction of local PGE₂ synthesis and the promotion of a pro-resolving and anti-inflammatory M2 macrophage phenotype via COX-2 signaling and involving FPR2.
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