The NLRP3 inflammasome: an emerging therapeutic target for chronic pain

Chen et al. Journal of Neuroinflammation https://doi.org/10.1186/s12974-021-02131-0 (2021) 18:84 REVIEW Open Access The NLRP3 inflammasome: an emerging therapeutic target for chronic pain Ruixiang Chen, Chengyu Yin, Jianqiao Fang* and Boyi Liu* Abstract Chronic pain affects the life quality of the suffering patients and posts heavy problems to the health care system. Conventional medications are usually insufficient for chronic pain management and oftentimes results in many adverse effects. The NLRP3 inflammasome controls the processing of proinflammatory cytokine interleukin 1β (IL-1β) and is implicated in a variety of disease conditions. Recently, growing number of evidence suggests that NLRP3 inflammasome is dysregulated under chronic pain condition and contributes to pathogenesis of chronic pain. This review provides an up-to-date summary of the recent findings of the involvement of NLRP3 inflammasome in chronic pain and discussed the expression and regulation of NLRP3 inflammasome-related signaling components in chronic pain conditions. This review also summarized the successful therapeutic approaches that target against NLRP3 inflammasome for chronic pain treatment. Keywords: NLRP3, Caspase-1, Inflammasome, Inflammation, Interleukins, Pain Introduction Pain accompanies with many chronic diseases. Chronic pain due to tissue inflammation, nerve lesion, tumor invasion, or chemotherapy represents a major health problem in the health care system [1]. Chronic pain is among the most common complaints in outpatient clinic [2]. It is estimated that 11–40% of adult population suffers from chronic pain [1]. Moreover, chronic pain is usually accompanied with emotional changes, including anxiety, depression, or even suicidal tendencies [2]. Therefore, chronic pain dramatically affects the life quality and posts heavy economic and social burdens to the suffering patients. However, conventional treatments for chronic pain are still limited to nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, corticosteroids, antidepressants, etc. These medications are usually insufficient for relieving chronic pain and often bring in many severe side effects [2, 3]. * Correspondence: ; Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, 548 Binwen Road, Hangzhou 310053, China A large body of evidence indicates that inflammatory mediators (e.g., proinflammatory cytokines) in local inflamed tissues, peripheral nerves, and spinal cord make important contributions to the initiation and maintenance of chronic pain [3–5]. Among these proinflammatory cytokines, IL-1β is the most extensively studied cytokines. It exerts robust proinflammatory effects on many types of immune cells and tissues, whereas its excessive production is implicated in the pathophysiology of acute or chronic inflammation and pain. IL-1β may contribute to pain via direct and indirect mechanisms. On the one hand, IL-1β directly activates nociceptors to elicit action potentials and induce pain [6]. On the other hand, IL-1β contributes to peripheral or central sensitization by sensitizing nociceptors or promoting neuron-glia crosstalk [7–9]. Inhibition of IL-1β signaling has been shown to be effective for ameliorating pain in both animal models and human patients. Due to its important physiological function, the production of the active form of IL-1β is usually under tight regulation. One of the important mechanisms underlying such regulation is mediated via NLRP3 inflammasome. © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chen et al. Journal of Neuroinflammation (2021) 18:84 NLRP3 inflammasome and its activation mechanism The NLRP3 inflammasome consists of NLRP3, ASC adaptors, and caspase-1 enzymes [10, 11]. The NLRP3 inflammasome is present primarily in immune and inflammatory cells, including mast cells, neutrophils, and macrophages, following activation by inflammatory stimuli [12–14]. Recent studies also identified NLRP3 inflammasome in neurons of the sensory nerve system [15]. NLRP3 inflammasome can be activated by a variety of stimuli and ligands, including PAMPs (pathogen associated molecular patterns), such as exogenous microbial molecules and bacterial lipopolysaccharide (LPS), and DAMPs (damage associated molecular patterns), such as HMGB1, S100 proteins, ATP, IL-33, and monosodium urate (MSU) [16, 17]. The activation procedure of NLRP3 inflammasome usually involves two phases (Fig. 1). The first phase is the priming phase, mediated primarily by Toll-like receptors (TLRs) and cytokine receptors (e.g., tumor necrosis factor receptor (TNFR)), which recognize PAMPs, DAMPs, or endogenous cytokines. This process results in upregulation of inactive NLRP3 and pro-IL-1β transcription via nuclear factor kappa B (NF-κB)-mediated transcriptional regulation [25]. MyD88 and TRIF, two downstream adaptor molecules of TLRs, regulate the induction of NLRP3 and pro-IL-1β transcription in response to TLR ligands during priming phase. The second phase involves the assembly of NLRP3 with ASC into the inflammasome complex, initiated by the stimulation of NLRP3 by a plethora of stimuli, including Ca+ influx, K+ efflux, mitochondrial damage, and ATP, and subsequent activation of procaspase-1 with autocatalytic activity (Fig. 1) [25]. The active caspase-1 ultimately cleaves pro-IL-1β and pro-IL-18, leading to maturation and release of IL-1β and IL-18 with proinflammatory activities [25]. The dysregulation of NLRP3 inflammasome has been shown to be related with a variety of diseases, including multiple sclerosis, diabetes, atherosclerosis, Alzheimer’s disease, inflammatory bowel disease, and many other autoimmune diseases [26]. More recently, growing number of evidence suggests that NLRP3 inflammasome is dysregulated under chronic pain conditions and contributes to the path (...truncated)