Inflammasomes: Role in disease pathogenesis and therapeutic potential
E.E. Garanina*, E.V. Martynova**, K.Y. Ivanov***, A.A. Rizvanov****, S.F. Khaiboullina*****
Kazan Federal University, Kazan, 420008 Russia
E-mail: *kathryn.cherenkova@gmail.com, **ignietferro.venivedivici@gmail.com,
***kos.ivanoff2010@yandex.ru, ****rizvanov@gmail.com, *****sv.khaiboullina@gmail.com
Received October 10, 2019
DOI: 10.26907/2542-064X.2020.1.80-111
For citation: Garanina E.E., Martynova E.V., Ivanov K.Y., Rizvanov A.A., Khaiboullina S.F. Inflammasomes: Role in disease pathogenesis and therapeutic potential. Uchenye Zapiski Kazanskogo Universiteta. Seriya Estestvennye Nauki, 2020, vol. 162, no. 1, pp. 80–111. doi: 10.26907/2542-064X.2020.1.80-111. (In Russian)
Abstract
The structure of inflammasomes, history of their discovery, and their potential use as therapeutic targets were discussed. Inflammasomes represent cytosolic polyprotein complexes that are formed in response to various external and internal stimuli, including viral and bacterial infections. The main products of inflammasomes are pro-inflammatory cytokines: interleukin-1-beta (IL-1β) and interleukin-18 (IL-18). Both cytokines are formed through proteolytic cleavage by active caspase-1. Caspase-1 activation leads to a special form of cell death called pyroptosis. Depending on external stimuli (bacterial, viral infections, cell damage, changes in ion concentration), various types of inflammasomes are activated. The possibilities of using caspase-1 inhibitors and other drugs in medicine were described.
Keywords: inflammasomes, caspase-1, cryopyrin, NOD receptors, inflammation, cytokines, pyroptosis
Acknowledgments. The study was supported by the grant of the President of the Russian Federation (project no. MK-2393.2019.4) and performed according to the Russian Government Program of Competitive Growth of Kazan Federal University. A.A. Rizvanov's research was funded by the state assignment no. 0671-2020-0058 of the Ministry of Science and Higher Education of the Russian Federation.
Figure Captions
Fig. 1. Schematic structure of the inflammasome. A – NLRP1 inflammasome is activated in response to the lethal toxin B. anthracis and muramyldipeptide (MDP). B – NLRP3 inflammasome is activated upon ingestion of viral RNA, as well as various danger signals, C – the mechanism of NLRP6 inflammasome activation is poorly understood.
Fig. 2. Schematic structure of the inflammasome: A – NLRC4 inflammasome is activated upon detection of gram-negative bacteria; B – AIM-2 inflammasome is activated upon detection of double-stranded DNA.
Fig. 3. Scheme of canonical (A) and non-canonical (B) signaling pathways of the inflammasomes: A – canonical activation of inflammasomes (canonical signaling pathways). (i) Lipopolysaccharide (LPS) is recognized by TLR4, (ii) activating the NF-κB signaling pathway, (iii) resulting in an increase in the transcription level of inactive pro-IL-1β, pro-IL-18, and pro-caspase-11 precursors (iv). A secondary inflammatory signal (eg, PAMP or DAMP) triggers the formation of an inflammasoma (vi). Hydrolysis and activation of pro-caspase-1, pro-IL-1β, and pro-IL-18 occurs, (vii) with further secretion of IL-1β and IL-18 from the cell; B – non-canonical activation by inflammasome. (i) With an excessive content of free LPS or in vacuoles, LPS is able to penetrate into the intracellular space independently of TLR4. (ii) Guanilate-binding proteins (GBPs) ensure vacuole lysis, thereby helping LPS to enter the cytosol of the cell. (iii) Pro-caspase-11 detects cytosolic LPS (iv), initiating inflammasome assembly and pyroptosis (v). (vi) Assembly of the NLRP3-inflammasome also results in the secretion of IL-1β and IL-18, characteristic of the canonical signaling pathway.
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