Browsing by Subject "IL 18"

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    Extracellular ATP activates the NLRP3 inflammasome and is an early danger signal of skin allograft rejection
    (Elsevier, 2017-12-19) Amores Iniesta, Joaquín; Barberá Cremades, María; Parrilla, Pascual; Baroja Mazo, Alberto; Martínez Cáceres, Carlos Manuel; Pelegrín Vivancos, Pablo; Anatomía y Anatomía Patológica Comparadas
    Immune cells are equipped with a number of receptors that recognize sterile injury and pathogens. We find that host immune cells release ATP as an inflammatory signal in response to allogeneic transplantation. ATP then acts via a feedback mechanism on the P2X7 channel to activate the NLRP3 inflammasome and subsequently process and release interleukin (IL)-18. This process is a necessary stage in the deleterious Th1 response against allotransplantation via interferon-γ production. Lack of IL-18 resulted in a decrease in graft-infiltrating CD8 cells but an increase in regulatory T cells. In human liver transplant patients undergoing progressive immunosuppressive drug withdrawal, we found that patients experiencing acute rejection had higher levels of the P2X7 receptor in circulating inflammatory monocytes compared to tolerant patients. These data suggest that the pharmacological inhibition of the P2X7 receptor or the NLRP3 inflammasome will aid in inducing transplant tolerance without complete immunoparalysis.
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    Priming is dispensable for NLRP3 inflammasome activation in human monocytes in vitro
    (Frontiers Media, 2020-09-30) Martín Sánchez, María Rosario Fátima; Gritsenko, Anna; Yu, Shi; Díaz del Olmo, Inés; Nichols, Eva María; Davis, Daniel M.; Brough, David; López Castejón, Gloria; Farmacología
    Interleukin (IL)-18 and IL-1b are potent pro-inflammatory cytokines that contribute toinflammatory conditions such as rheumatoid arthritis and Alzheimer’s disease. They areproduced as inactive precursors that are activated by large macromolecular complexescalled inflammasomes upon sensing damage or pathogenic signals. NLRP3inflammasome activation is regarded to require a priming step that causes NLRP3 andIL-1b gene upregulation, and also NLRP3 post-translational licencing. A subsequentactivation step leads to the assembly of the complex and the cleavage of pro-IL-18 andpro-IL-1b by caspase-1 into their mature forms, allowing their release. Here we show thathuman monocytes, but not monocyte derived macrophages, are able to form canonicalNLRP3 inflammasomes in the absence of priming. NLRP3 activator nigericin caused theprocessing and release of constitutively expressed IL-18 in an unprimed setting. This wasmediated by the canonical NLRP3 inflammasome that was dependent on K + and Cl−efflux and led to ASC oligomerization, caspase-1 and Gasdermin-D (GSDMD) cleavage.IL-18 release was impaired by the NLRP3 inhibitor MCC950 and by the absence ofNLRP3, but also by deficiency of GSDMD, suggesting that pyroptosis is the mechanism ofrelease. This work highlights the readiness of the NLRP3 inflammasome to assemble inthe absence of priming in human monocytes and hence contribute to the very early stagesof the inflammatory response when IL-1b has not yet been produced. It is important toconsider the unprimed setting when researching the mechanisms of NLRP3 activation, asto not overshadow the pathways that occur in the absence of priming stimuli, which mightonly enhance this response.