Background/Purpose:

The regenerative and immunomodulatory properties of Adipose-Derived Mesenchymal Stem Cells (ASCs) make them a potential therapeutic approach for the treatment of chronic inflammatory diseases, such as osteoarthritis and rheumatoid arthritis. However, their effect in the treatment of acute joint inflammation, where the activation mostly depends on innate immunity, remains elusive. Gouty arthritis is characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated with acute flares. Frustrated phagocytosis of MSU crystals by resident leukocytes leads to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of ASCs administration in the clinical inflammatory response, and the molecular mechanisms involved.

Methods:

Acute gout flare was induced in 15 rabbits by intra-articular injection of MSU crystals in both knees. A single dose of 2.5×10⁶ ASCs/kg was administered to 7 of these rabbits through the right femoral artery 1h after MSU injection (MSU+ASC), whereas 8 animals were not treated (MSU). This route of administration allowed to study the effect of a direct ASC administration in the right knee synovial membrane (SM) and the contralateral knee, which received the cells after their distribution through the organism. Four rabbits were used as healthy (H) controls. Inflammation was followed up measuring knee swelling and serum CRP. Animals were sacrificed 72h after MSU injections, and SM were collected for further studies.

Results:

ASCs ameliorated joint swelling in both knees 24h after MSU injections, and a significant decrease in serum CRP was observed (H:73±51; MSU:818±238*; MSU+ASCs:270±241 mg/ml*#; p<0.05 *vs. H; # vs. MSU). Histopathological analysis showed that ASCs significantly diminished SM inflammation 72h after MSU injection (Krenn Score: H:0.2±0.4; MSU:5.6±2.3*, MSU+ASC:3.4±1.2*#). SM vascularization was also reduced in treated animals (%CD31+ staining: H 0.5±0.2; MSU 0.8±0.2*; MSU+ASC 0.6±0.2#). ASCs treatment evoked a reduction of the inflammasome components in the SM: pro-IL1β (H:0.9±0.2; MSU:1.5±0.5*; MSU+ASC:1.1±0.2*#), pro-caspase-1 (H:1±0.6; MSU:3.5±3.1*; MSU+ASC:1.4±0.5*#), NALP3 (H:1±0.3; MSU:2.9±2.1*; MSU+ASC:1.4±0.7*#), and NFkB activity was attenuated (H:0.12±0.01; MSU:0.22±0.07*; MSU+ASC:0.16±0.03*#). Synthesis of pro-inflammatory cytokines COX-2 (H 0.9±0.1; MSU 4.2±3.3*; MSU+ASC 2.1±1.4*#) and TNFα (H:0.9±0.3; MSU:1.3±0.3*; MSU+ASC:0.9±0.2*#) were also reduced in the MSU+ASC animals, while TGFβ (H:0.9±0.2; MSU:0.7±0.2*; MSU+ASC:1.3±0.3*#) and IL10 (H:1.1±0.5; MSU:1.1±0.7*; MSU+ASC:1.8±0.5*#) were increased in comparison to MSU group. No differences between the direct and the indirect treatment were found, since both right and left SMs were equally damaged.

Conclusion:

Our data showed that a single parenteral dose of ASCs is able to decrease the inflammatory response in an acute gouty arthritis model in rabbits by inhibiting NALP3 inflammasome activation. Therefore, this therapeutic approach may be considered for treating gouty flares, as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/parenteral-injection-of-human-adipose-derived-mesenchymal-stem-cells-attenuates-inflammation-in-an-acute-model-of-gouty-arthritis/