CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1

Abstract

Peripheral tissue damage leads to inflammatory pain, and inflammatory cytokine releasing is the key factor for inducing the sensitization of nociceptors. As a calcium ion channel, TRPA1 plays an important role in pain and inflammation, thus becoming a new type of anti-inflammatory and analgesic target. However, there is no consensus on the role of this channel in mechanical hyperalgesia caused by inflammation. Here, we aim to explore the role and underlying mechanism of the inflammasome inhibitor CY-09 in two classic inflammatory pain models. We evaluated pain behavior on animal models, cytokine levels, intracellular Ca2+ levels, transient TRPA1 expression, NF-κB transcription, and NLPR3 inflammasome activation. Consistently, CY-09 reduced the production of inflammatory cytokines, intracellular Ca2+ levels, and the activation of TRPA1 by inhibiting the activation of inflammasomes, thereby reducing the proinflammatory polarization of macrophages and alleviating animal pain and injury. Importantly, AITC (TRPA1 agonist) significantly reversed the analgesic effect of CY-09, indicating that TRPA1 was involved in the analgesic effect of CY-09. Our findings indicate that CY-09 relieves inflammation and pain via inhibiting TRPA1-mediated activation of NLRP3 inflammasomes. Thus, NLRP3 inflammasome may be a potential therapeutic target for pain treatment and CY-09 may be a pharmacological agent to relieve inflammatory pain, which needs further research.

The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

“…Using microscale thermophoresis (MST), CY-09 binds to recombinant NLRP3 with a K D of 500 nM (Jiang H. et al, 2017). CY-09 has shown to be effective in ex vivo and in vivo models for CAPS, type 2 diabetes, gout, non-alcoholic fatty liver disease (NAFLD), pain, and more (Jiang H. et al, 2017;Fan et al, 2021;Wang X. et al, 2021).…”

The Inflammasome NLR Family Pyrin Domain-Containing Protein 3 (NLRP3) as a Novel Therapeutic Target for Idiopathic Pulmonary Fibrosis

“…CY-09 reduces inflammation and pain via inhibiting transient receptor potential cation channel subfamily A member 1 (TRPA1)emediated activation of NLRP3 inflammasome in a mouse pain model. 94 In addition, there are multiple drugs that, through diverse mechanisms of action, inhibit the inflammasome NLRP3 (Table 1).…”

A Novel Progress: Glial Cells and Inflammatory Pain

“…The P2Y14 receptor participates in the sensitization of SGCs and phosphorylation of MAPKs, and promotion of IL-1β and CCL2 secretion through the ERK and P38 pathways; , peripherally released inflammatory mediators lead to the discharge of ATP from the dorsal root ganglion, activate the SGC’s P2X7R and trigger the release of IL-1β, induce inflammatory responses, enlarge or maintain neuronal activation, and increase pain behavior. , Studies have found that capsaicin receptor 1 (TRPA1) is expressed in SGCs. Nerve damage and peripheral inflammation produce the activation of SGC-TRPA1, improve the function of neuronal TRPA1, and promote the increase of primary afferent discharge in sustaining inflammation or neuropathic pain, suggesting that SGC-TRPA1 may be a new target for the treatment of chronic pain. − SGCs can cause inflammatory pain by releasing cytokines. Under physiological and inflammatory conditions, Hemokinin-1 released by SGCs participates in the inflammatory process and nociceptive sensitization of oral and facial pain through neuron–glia interactions .…”