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.

Hesperidin Methyl Chalcone Reduces the Arthritis Caused by TiO2 in Mice: Targeting Inflammation, Oxidative Stress, Cytokine Production, and Nociceptor Sensory Neuron Activation

“…In the Hargreaves test of thermal hyperalgesia, HMC, again, reduced the nociceptive effect of TiO 2 arthritis ( Figure 2 B). Similarly, HMC reduced the imbalance of hind paw weight distribution (right/left paw ratio values— Figure 2 C, and heat map— Figure 2 D), which is a measurement of non-evoked/spontaneous nociceptive behavior [ 33 ]. These results demonstrate—using varied methods—that HMC can reduce both evoked and non-evoked nociceptive behaviors triggered by articular inflammation initiated by the TiO 2 .…”

“…The articular mechanical hyperalgesia of the femorotibial joint was evaluated as previously described [ 33 ]. Briefly, in a quiet room, mice were placed individually in acrylic cages (12 × 10 × 17 cm) with a wire grid floor 15–30 min before the test for environmental adaption.…”

“…The test was repeated until the subsequent consistent measurements (i.e., the variation among these measurements was less than 1 g) were obtained. The flexion-elicited mechanical threshold was expressed in grams (g) [ 33 ].…”

Ehrlich Tumor Induces TRPV1-Dependent Evoked and Non-Evoked Pain-like Behavior in Mice

“…These polymodal nociceptors are involved in a great variety of painful conditions ranging from inflammatory pain to neuropathic pain, complex regional pain syndrome type 1, and cancer pain [ 32 , 33 ]. For instance, in inflammatory pain, in addition to neurotransmission of nociceptive inputs, TRPV1 + neurons, through the release of neuropeptides, participate in generating neurogenic inflammation and communicate with immune cells, regulating their recruitment and function such as phagocytosis [ 18 ]. Thus, TRPV1 + neurons have a role in immune regulation during disease.…”

“…To assess TRPV1 activation, DRG plates were recorded for a total time of 7 min, which was divided into: baseline values/initial reading (2 min), TRPV1 stimulation with its agonist capsaicin (100 nM in HBSS, MilliporeSigma, Burlington, MA, USA) for up to 4 min, and then KCl solution (final concentration was 40 mM) for the remainder of the recording time. The TCS SP8 confocal microscope used the LAS X Software (Leica Microsystems, Mannheim, Germany) [ 16 , 17 , 18 , 19 , 20 ], which was applied to analyze the mean fluorescence intensity representing calcium influx.…”