Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders

Abstract

The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.

Pretreatment of the ROS Inhibitor Phenyl-N-tert-butylnitrone Alleviates Sleep Deprivation-Induced Hyperalgesia by Suppressing Microglia Activation and NLRP3 Inflammasome Activity in the Spinal Dorsal Cord

“…Previous studies revealed that excessive ROS generation is associated with endoplasmic reticulum (ER) stress, which induces inflammatory response by activating the nuclear factor-kappa B (NF-κB) signaling pathway [34]. Oxidative stress is involved in the activation of NLRP3 inflammatory corpuscles, which is an important component of innate immunity involved in the process of inflammatory diseases of the CNS [35][36][37]. Latest studies have shown that NLRP3 is up-regulated in both neuropathic and inflammatory pain models, the activation of which, is also involved in the occurrence and maintenance of postoperative pain [38].…”

The Role of Microglia in Alzheimer’s Disease From the Perspective of Immune Inflammation and Iron Metabolism

“…Upon recognition of PAMPs or host-derived DAMPs, signals are transmitted to the immune system to initiate inflammation. Inflammasome promotes the maturation and secretion of pro-IL1β and pro-IL18 to produce IL-1β and IL-18 by causing the shearing and activation of Caspase-1 during the natural immune defense (Tastan et al, 2022). Several inflammasosomes have been identified, including NLRP1, NLRP3, NLRC4, and AIM2 (Cox et al, 2015;Friker et al, 2020).…”

Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis

“…The canonical pathway requires a priming step in the context of low intracellular levels of pro-inflammatory cytokines and NLRP3 that are insufficient to activate the inflammasome complex. The priming step is initiated via TLR4 receptors and leads to nuclear translocation of NFκB, resulting in the transcription of pro-inflammatory cytokines genes [201]. In the activation step, sensor proteins such as NLRP3, recognize various danger signals and interact with ASC via its PYD domain.…”