RvD1 disrupts nociceptor neuron and macrophage activation and neuroimmune communication, reducing pain and inflammation in gouty arthritis in mice.

Abstract

BACKGROUND AND PURPOSE:

Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in reducing gout-related pain. Resolvin D1 (RvD1) is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature.

EXPERIMENTAL APPROACH:

Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL-1β production was measured by ELISA. Phosphorylated NF-kB and apoptosis-associated speck-like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT-qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy.

KEY RESULTS:

RvD1 inhibited MSU-induced mechanical hyperalgesia in a dose- and time-dependent manner by reducing leukocyte recruitment and IL-1β production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL-1β production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP-dependent activation of macrophages.

CONCLUSIONS AND IMPLICATIONS:

This study reveals a hitherto unknown neuro-immune axis in gouty arthritis that is targeted by RvD1.

• Authors: Tiago H Zaninelli, Victor Fattori, Telma Saraiva-Santos, Stephanie Badaro-Garcia, Larissa Staurengo-Ferrari, Ketlem C Andrade, Nayara A Artero, Camila R Ferraz, Mariana M Bertozzi, Fernanda Rasquel-Oliveira, Marilia F Manchope, Flávio A Amaral, Mauro M Teixeira, Sergio M Borghi, Michael S Rogers, Rubia Casagrande, Waldiceu A Verri Jr
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 18 Pg. 4500-4515 (09 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 35716378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 British Pharmacological Society.

Chemical References

• resolvin D1
• Docosahexaenoic Acids
• Uric Acid
• Calcitonin Gene-Related Peptide

Topics

• Animals
• Arthritis, Gouty (chemically induced, drug therapy)
• Calcitonin Gene-Related Peptide
• Docosahexaenoic Acids
• Hyperalgesia (drug therapy, metabolism)
• Inflammation (metabolism)
• Macrophage Activation
• Male
• Mice
• Neuroimmunomodulation
• Neurons
• Nociceptors (metabolism)
• Pain
• Uric Acid (chemistry, pharmacology)