Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Inflammation is a protective immune response which helps to combat harmful entities like pathogens, irritants or dead cells. Inflammation is a highly regulated process and once it becomes deregulated, it may lead to many pathological conditions [78]. Innate immune response can be elicited by pathogen derived molecules, pathogen associated molecular patterns (PAMPs), or by danger-associated molecular patterns (DAMPs) generated through endogenous stress [78]. Inflammasome is a multiprotein complex, based on physiological and pathogenic stresses, responsible for the induction of inflammatory response. Inflammasome contains nucleotide-binding domain-like receptors (NLRs), absent in melanoma (AIM) and a zymogen, procaspase-1. Assembly of inflammasome leads to the activation of caspase-1, which enzymatically cleaves precursors of IL-1β and IL-18 to orchestrate the downstream inflammatory signals [78, 79]. Inflammasome-mediated immune response is highly regulated and it has been suggested that activation of NF-κB signaling pathway is required for the activation of NLRP3 inflammasome [80]. Recently, it has been shown that NF-κB signaling pathway can control excessive inflammatory response by restraining NLRP3 mediated inflammasome activation by inducing p62 dependent autophagy [81].
Etiopathogenesis
Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan in Comprehensive Textbook on Vitiligo, 2020
Inflammasome is constitutive of the innate immune system and is responsible for regulating the immunological response to several stimuli. It consists mainly of a molecular pattern recognition receptor, an apoptosis-associated speck-like protein, which contains a caspase-recruitment domain adaptor protein, and a caspase-1 enzyme [19]. Recent reports identified single-nucleotide polymorphisms in the promoter and coding regions of NLR family pyrin domain containing 1 (Nlrp1) associated with vitiligo, vitiligo-associated autoimmune diseases, Addison disease, and type I diabetes [19]. Nlrp1 is highly expressed in T cells and Langerhans cells in the skin, explaining the potential role of mutant Nlrp1 in autoimmune diseases of the skin. This ultimately results in depigmentation in irregular patches of the skin and hair [19].
Flavonoids with Preclinical Antidepressant-Like Effects
Scott Mendelson in Herbal Treatment of Major Depression, 2019
Flavonoids have also been found to inhibit, directly or indirectly, activation of the NLRP3 inflammasome. The inflammasome is a multi-protein complex that regulates major components of the inflammatory response, including caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to a variety of stimuli, including infection, oxidative damage, and physical injury, but also psychological stress. Among the NLRs, NLRP3 senses the widest array of stimuli. The flavonoid apigenin has been found to inhibit lipopolysaccharide-induced synthesis of the inflammatory cytokine IL-1β by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly.102 Luteoloside also decreases expression of NLRP3 inflammasome resulting in decreases in proteolytic activation of caspase-1. Inactivation of caspase-1 in turn results in inhibition of IL-1β production.103
NLRP3 inflammasome activation increases brain oxidative stress after transient global cerebral ischemia in rats
Published in International Journal of Neuroscience, 2023
Larissa Silva Joaquim, Lucinéia Gainski Danielski, Sandra Bonfante, Erica Biehl, Khiany Mathias, Tais Denicol, Erick Bagio, Everton Venicius Lanzzarin, Richard Simon Machado, Gabriela Costa Bernades, Jaqueline Generoso, Amanda Della Giustina, Tatiana Barichello, Fabricia Petronilho
Inflammasomes are a group of high molecular weight protein complexes present in the cytosol that are formed to mediate host immune responses to microbial infection and cell damage [13]. The inflammasome NLR family pyrin domain containing 3 (NLRP3) is widely expressed in glial cells being a key molecule in neuroinflammation processes [14]. NLRP3 is established as a sensor that detects cell damage and modulates inflammatory responses to injury [15]. Evidences point that oxidative stress is implicated in the activation of NLRP3 [16,17], and the inhibition of NLRP3 by MCC950, a selective NLRP3 inhibitor, may protect the brain against neuroinflammation due to I/R injuries [18]. However, the mechanisms exerted by MCC960 on the inhibition of NLRP3 and controlling neurochemical alterations, such as oxidative stress, in cerebral ischemia are not yet fully elucidated.
Tectoridin alleviates lipopolysaccharide-induced inflammation via inhibiting TLR4-NF-κB/NLRP3 signaling in vivo and in vitro
Published in Immunopharmacology and Immunotoxicology, 2022
Xiaofeng Niu, Huixin Song, Xin Xiao, Jinjin Yu, Jiabao Yu, Yajie Yang, Qiuxia Huang, Lulu Zang, Tengfei Han, Dezhu Zhang, Weifeng Li
Inflammasome, a large intracellular multi-protein signal complex, has been suggested involved in the pathogenesis of sepsis [51]. NLRP3 inflammasome is a multi-protein complex, which is related to a variety of inflammatory and autoimmune diseases [52]. Thus, the NLRP3 inflammasome may be a promising target for anti-inflammatory therapies. Our study showed that the anti-inflammatory effect of tectoridin may associate with its ability to inhibit NLRP3 inflammasome inappropriate activation. There are two ways for the activation of NLRP3 inflammasome as previously explained, the TLR-induced NF-κB activation and the NLRP3 activation, which eventually lead to proteolytic cleavage of inactive pro-caspase-1 into active caspase-1. Subsequently, the active caspase-1 in turn induces the cytokine precursors pro-IL-1β and pro-IL-18 into mature and bioactive IL-1β and IL-18, respectively [53,54]. And then they secreted into the inflammatory environment, inducing the inflammatory forms of cell death termed pyroptosis [17]. Our experimental dates showed that pretreatment with tectoridin dramatically suppressed LPS-upraised the levels of NLRP3, caspase-1, and IL-1β both at western blot and immunohistochemistry levels, which is consistent with its effect of inhibiting the expression of IL-1β and IL-18.
Effect of NLRP3 repression on NLRP3 inflammasome activation in human corneal epithelial cells with black carbon exposure
Published in Cutaneous and Ocular Toxicology, 2022
Kang Xiao, Jing Shang, Ying Liu, Zhengyu Chen, Liqiang Wang, Qin Long
Inflammasomes are a group of multimeric protein complexes that mediate the immune responses against pathogen infection and tissue damage25. During the activation process of the NLRP3 inflammasome, NLRP3 acts as an initiator protein to respond to the disturbance of tissue homeostasis, further recruiting adaptor protein ASC. As a platform, the clustered ASC can mediate Caspase-1 activation followed by increases in proinflammatory cytokine expressions, such as IL-1β and IL-1826,27. Our study showed NLRP3-siRNA could partially suppress the NLRP3 and ASC protein levels in FBC or OBC treated HCECs to influence the priming step of activation, which may further inhibit the inflammasome activation. Moreover, the reduction of protein level of Caspase-1 and IL-1β was not significant in the NLRP3 siRNA transfected group, indicating the inhibitory effect of NLRP3-siRNA on NLRP3 inflammasome activation by BC was limited. These results were probably because NLRP3 is an important but not exclusive mediator of BC-induced caspase-1 and IL-1β overexpression and Caspase-1 and IL-1β could be mediated by other inflammasomes or by inflammasome-independent pathways28–30. Another possible explanation was that the silencing effectiveness of NLRP3-siRNA on NLRP3 mRNA expression was not 100%, the residual NLRP3 gene expressions with BC treatment increased Caspase-1 and IL-1β levels via activation of NLRP3 inflammasome, which may overcome the inhibitory effect of NLRP3 siRNA.
Related Knowledge Centers
- Innate Immune System
- Interleukin 18
- Oligomer
- Pyroptosis
- Cell Membrane
- Apoptosis
- Cytokine
- Cytosol
- Protein Complex
- Interleukin 1 Beta