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Inflammatory bowel disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Giovanni Monteleone, Markus F. Neurath, Britta Siegmund
The synthesis and secretion of pro-inflammatory cytokines are governed by germline-encoded receptors such as the TLRs and nucleotide-binding-domain and LRR-containing (NLR) proteins that can be activated by microbe- associated molecular patterns (MAMPs). For example, the production of active (mature) IL-1β and IL-18 occurs through a two-step process initiated by the transcriptional induction of a procytokine (e.g., a TLR stimulus) followed by caspase 1–mediated cleavage. In this process, NLRP3, also known as cryopyrin, associates with the NLR adaptor protein, apoptotic speck protein containing a CARD domain (ASC/PYCARD), to recruit procaspase 1. This complex is referred to as the inflammasome, and leads to the processing of procaspase 1 into active caspase 1. Caspase 1 is responsible for the subsequent cleavage of the IL-1β/IL-18 precursors into their functional forms. In addition to NLRP3, other NLRs, including NLRP1, NLRC4, and NAIP, also function in caspase-1 activation and IL-1β production through the formation of other inflammasomes in response to distinct sets of stimuli. Mice lacking NLRP3, ASC, or caspase 1 produce reduced levels of IL-1β and TNF-α and are protected from inflammation in acute, but not necessarily chronic, experimental colitis, suggesting that the NLRP inflammasome has a more critical role during the early phase of colitis.
Flavonoids with Preclinical Antidepressant-Like Effects
Published in Scott Mendelson, 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
Apoptosis and Cell Death
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
There are two signalling pathways that result in apoptosis, the mitochondrial (intrinsic) and the death receptor (extrinsic) pathways. Both involve activation of a family of enzymes called the caspases. Caspases are cysteine proteases that cleave after aspartic acid residues. Caspases are named in the order of their discovery, and while caspases 1, 4 and 5 are involved primarily in the processing of inflammatory mediators, caspases 2, 8, 9 and 10 have roles as initiator caspases for cell death signals, activating downstream effector caspases 3, 6 and 7, which target cellular proteins leading to the condensation of the cell and dissolution of the nuclear membrane. Hundreds of proteins are cleaved by caspases, usually at single sites. Some are cleaved as bystanders, but many structural and regulatory proteins are inactivated by caspases. Some substrates can be activated by cleavage – such as other caspases and Bid (see the section ‘Death Receptor Pathway to Apoptosis’ below). By cleavage of an inhibitor protein (ICAD), they release a caspase-activated deoxyribonuclease (CAD) that cleaves the DNA of the cell into oligomeric fragments that are integer multiples of 180–200 base pairs. This cleavage pattern can be detected on DNA electrophoresis as a ‘DNA ladder’. The cleavage of DNA ensures that the cell is no longer capable of replication, and the destruction of the translational machinery restricts protein synthesis.
Human umbilical cord mesenchymal stem cell exosomes alleviate acute kidney injury by inhibiting pyroptosis in rats and NRK-52E cells
Published in Renal Failure, 2023
Yonghong Wan, Yihang Yu, Chengjun Yu, Jin Luo, Sheng Wen, Lianju Shen, Guanghui Wei, Yi Hua
Pyroptosis is a form of proinflammatory programmed cell death characterized by nuclear shrinkage, the formation and rupture of plasma membrane pores, and inflammatory response [15,16]. It is distinct from apoptosis and necrosis [17]. Pyroptosis is promoted by the NLRP3 inflammasome, a complex assembly. When the NLRP3 inflammasome is activated, caspase-1 is cleaved, and gasdermin D (GSDMD) is cleaved, proinflammatory cytokines are released, and pyroptosis occurs [18]. Activation of caspase-1 is the classical pyroptosis pathway. It induces the inflammatory cell death and secretion of the proinflammatory cytokines interleukin (IL)-18 and IL-1β, thereby promoting removal of pathogens and tissue repair [19]. During AKI, pyroptosis plays a crucial role [20,21]. Hence, we aimed to investigate how exosomes affect pyroptosis during AKI.
Caspase-1 inhibition by YVAD generates tregs pivoting IL-17 to IL-22 response in β-glucan induced airway inflammation
Published in Immunopharmacology and Immunotoxicology, 2022
Divyesh Patel, Naveen Challagundla, Dipeeka Mandaliya, Shivani Yadav, Omkar Naik, Parameswar Dalai, Dhruvi Shah, Hima Vora, Reena Agrawal-Rajput
In this study, to emphasize the role of inflammasome and elucidate the beneficiary roles of its inhibition, we have inhibited caspase-1, the conclusive target for inflammasome pathways. We show that caspase-1 inhibition inhibited pro-inflammatory cytokines. YVAD, inhibitor of caspase-1 did not affect the dectin-1 expression. Contrast to our previous observation that SYK inhibition decreased Th1 priming pro-inflammatory cytokines, caspase-1 inhibition did not alter much of these cytokines. However, it enhanced the secretion of anti-inflammatory and resolving cytokines. This strategy has an advantage over SYK inhibition, as it only inhibits the inflammasome-mediated response, without significantly affecting the Th1 axis. Caspase-1 inhibition results in increased release of IL-10 and TGF-β, indicating the switch of immune response toward resolution phase (Figure 7).
Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis
Published in Toxicology Mechanisms and Methods, 2021
Liping Jiang, Songsong Luo, Tianming Qiu, Qiannan Li, Chunteng Jiang, Xiance Sun, Guang Yang, Cong Zhang, Xiaofang Liu, Lijie Jiang
Recent studies have demonstrated that acrolein could result in cell death and apoptosis in a variety of cells, such as acrolein-induced cardiomyocyte apoptosis (Wang et al. 2011), rapamycin inhibited acrolein-induced apoptosis in male germ cells (He et al. 2014). Pyroptosis is inflammatory programmed cell death, accompanying by pore formation, cell swelling, and inflammasome activation. Recent studies showed that acrolein can cause an inflammatory response in different cells and tissues including endothelial cells (Sun et al. 2014). However, the underlying mechanism is unknown. Caspase-1 plays a fundamental role in several important inflammatory diseases act as the protease of the pro-inflammatory cytokines pro-IL-1β. Therefore, we hypothesized that pyroptosis may be one of the mechanisms by which acrolein induces inflammation. The measurement of LDH release, dead cell staining, and caspase-1 activation has been used to confirm pyroptosis (Wree et al. 2014; Yang et al. 2014). Our results revealed that acrolein induced cell death as indicated by dead cell staining and increased LDH. Based on Western blot analysis, the protein levels of NLRP3, caspase-1, and IL-1β were increased significantly after acrolein treatment. NLRP3 siRNA treatment resulted in a significant decrease in cleaved caspase-1 expression (Figure 3). All of these data illustrated that pyroptosis is triggered by acrolein in EAhy926 cells and NLRP3 inflammasome was required for this process. These findings have provided a new therapeutic target (NLRP3) for acrolein-induced cardiovascular diseases.