Molecular mechanisms of pain in crystal-induced arthritis

Ramonda, Roberta; Oliviero, Francesca; Galozzi, Paola; Frallonardo, Paola; Lorenzin, Mariagrazia; Ortolan, Augusta; Scanu, Anna; Punzi, Leonardo

doi:10.1016/j.berh.2015.04.025

Cited by 28 publications

(16 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pain is the most dominant symptom during gout flares. Afferent nerve endings innervate joints, including C and Aδ fibers, and different factors are associated to the hypersensitization of nociceptors during gouty inflammation, such as prostaglandin E2, bradykinin, substance P, and cytokines . The expression of PI3Kγ has been identified in nociceptive afferent neurons in mice .…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout

Tavares

Galvão

Costa

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

This study investigates the participation of PI3Kγ in the development of joint inflammation and dysfunction in an experimental model of acute gout in mice. Acute gout was induced by injection of monosodium urate (MSU) crystals into the tibiofemoral joint of mice. The involvement of PI3Kγ was evaluated using a selective inhibitor and mice deficient for PI3Kγ (PI3Kγ−/−) or with loss of kinase activity. Neutrophils recovered from the inflamed joint were quantified and stained for phosphorylated Akt (pAkt) and production of reactive oxygen species (ROS). The adherence of leukocytes to the joint microvasculature was assessed by intravital microscopy and cleaved caspase‐1 by Western blot. Injection of MSU crystals induced massive accumulation of neutrophils expressing phosphorylated Akt. In the absence of PI3Kγ, there was reduction of pAkt expression, chemokine production, and neutrophil recruitment. Genetic or pharmacological inhibition of PI3Kγ reduced the adherence of leukocytes to the joint microvasculature, even in joints with established inflammation. Neutrophils from PI3Kγ−/− mice produced less ROS than wild‐type neutrophils. There was decreased joint damage and dysfunction in the absence of PI3Kγ. In addition, in the absence of PI3Kγ activity, there was reduction of cleaved caspase‐1 and IL‐1β production in synovial tissue after injection of MSU crystals and leukotriene B4. Our studies suggest that PI3Kγ is crucial for MSU crystal–induced acute joint inflammation. It is necessary for regulating caspase‐1 activation and for mediating neutrophil migration and activation. Drugs that impair PI3Kγ function may be useful to control acute gout inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout

Tavares

Galvão

Costa

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

“…The most commonly used therapies for acute gout in general practice include the use of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids. Although these drugs have certain therapeutic effects, they present serious side effects, such as liver and kidney damage and severe gastrointestinal reactions [3, 4, 28]. Moreover, the treatment of gout is often a long-term process.…”

Section: Discussionmentioning

confidence: 99%

“…Acute symptoms of gout patients include redness, swelling, heat, pain, and even joint functional loss [2]. Gout pain is undoubtedly one of the most serious symptoms and can be extreme, even disabling [3]. Therefore, the development of efficient analgesia for gout pain is of very important clinic significance.…”

Section: Introductionmentioning

confidence: 99%

Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression

Liu

Pan

Liu

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundGout is one of the common inflammatory arthritis which affects many people for inflicting unbearable pain. Macrophage-mediated inflammation plays an important role in gout. The uptake of monosodium urate (MSU) crystals by macrophages can lead to activation of NOD-like receptors containing a PYD 3 (NLRP3) inflammasome, thus accelerating interleukin (IL)-1β production. Reactive oxygen species (ROS) promoted development of the inflammatory process through NLRP3 inflammasome. Our study aimed to find a food-derived compound to attenuate gout pain via the specific inhibition of the NLRP3 inflammasome in macrophages.MethodsCD-1 mice were used to evaluate the degree of pain and the swelling dimension of joints after an intra-articular (IA) MSU injection in the ankle. The murine macrophage cell line Raw 264.7 was used to investigate the effects of procyanidins and the mechanism underlying such effects. Histological analysis was used to measure the infiltration of inflammatory cells. ROS produced from Raw 264.7 cells were evaluated by flow cytometry. Cell signaling was measured by Western blot assay and immunofluorescence.ResultsProcyanidins significantly attenuated gout pain and suppressed ankle swelling. Procyanidins also inhibited MSU-induced activation of the NLRP3 inflammasome and increase of IL-1β. Furthermore, procyanidins decreased ROS levels in Raw 264.7 cells.ConclusionsSuppression of the NLRP3 inflammasome in macrophages contributes to the amelioration of gout pain by procyanidins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0849-y) contains supplementary material, which is available to authorized users.

show abstract

“…Severe acute pain is considered the most important clinical symptom in patients suffering from crystal-induced arthritis (CIA). Ramonda et al [73], evaluating this phenomenon, demonstrated that bradykinin can be included as one of the most important molecules to induce pain, together with prostaglandins, cytokines (in particular, interleukin-1β) and substance P, exerting their effects through different receptors present in both peripheral sensory neurons and in the spinal cord. De Falco et al [74] reviewed the importance of bradykinin to osteoarthritis and described the action of B 2 receptor antagonists to this condition, presenting these antagonists as promising agents to the osteoarthritis treatment.…”

Section: Discussionmentioning

confidence: 99%

Articular inflammation induced by an enzymatically-inactive Lys49 phospholipase A2: activation of endogenous phospholipases contributes to the pronociceptive effect

Dias

Sampaio

Sant’Anna

et al. 2017

J Venom Anim Toxins Incl Trop Dis

View full text Add to dashboard Cite

BackgroundArthritis is a set of inflammatory conditions that induce aching, stiffness, swelling, pain and may cause functional disability with severe consequences to the patient’s lives. These are multi-mediated pathologies that cannot be effectively protected and/or treated. Therefore, the aim of this study was to establish a new model of acute arthritis, using a Lys49-PLA2 (Bothrops asper myotoxin II; MT-II) to induce articular inflammation.MethodsThe articular inflammation was induced by MT-II (10 μg/joint) injection into the left tibio-tarsal or femoral-tibial-patellar joints. Cellular influx was evaluated counting total and differential cells that migrated to the joint. The plasma extravasation was determined using Evans blue dye. The edematogenic response was evaluated measuring the joint thickness using a caliper. The articular hypernociception was determined by a dorsal flexion of the tibio-tarsal joint using an electronic pressure-meter test. The mediators involved in the articular hypernociception were evaluated using receptor antagonists and enzymatic inhibitors.ResultsPlasma extravasation in the knee joints was observed 5 and 15 min after MT-II (10 μg/joint) injection. MT-II also induced a polymorphonuclear cell influx into the femoral-tibial-patellar joints observed 8 h after its injection, a period that coincided with the peak of the hyperalgesic effect. Hyperalgesia was inhibited by the pretreatment of the animals with cyclooxygenase inhibitor indomethacin, with type-2 cyclooxygenase inhibitor celecoxib, with AACOCF3 and PACOCF3, inhibitors of cytosolic and Ca2+-independent PLA2s, respectively, with bradykinin B2 receptor antagonist HOE 140, with antibodies against TNFα, IL-1β, IL-6 and CINC-1 and with selective ET-A (BQ-123) and ET-B (BQ-788) endothelin receptors antagonists. The MT-II-induced hyperalgesia was not altered by the lipoxygenase inhibitor zileuton, by the bradykinin B1 receptor antagonist Lys-(Des-Arg9,Leu8)-bradykinin, by the histamine and serotonin antagonists promethazine and methysergide, respectively, by the nitric oxide inhibitor LNMMA and by the inhibitor of matrix 1-, 2-, 3-, 8- and 9- metalloproteinases GM6001 (Ilomastat).ConclusionThese results demonstrated the multi-mediated characteristic of the articular inflammation induced by MT-II, which demonstrates its relevance as a model for arthritis mechanisms and treatment evaluation.

show abstract

Molecular mechanisms of pain in crystal-induced arthritis

Cited by 28 publications

References 78 publications

Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout

Phosphoinositide-3 kinase gamma regulates caspase-1 activation and leukocyte recruitment in acute murine gout

Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression

Articular inflammation induced by an enzymatically-inactive Lys49 phospholipase A2: activation of endogenous phospholipases contributes to the pronociceptive effect

Contact Info

Product

Resources

About