Inflammasome
Inflammasomes are cytosolic multiprotein complexes of the innate immune system that are responsible for activating inflammatory reactions . Activation of the inflammasome and formation of the multiprotein complex lead to proteolytic cleavage, maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). Gasdermin-D is also cleaved, the N-terminal fragment of which then induces a special form of pro-inflammatory cell death called pyroptosis . Gasdermin-D is also responsible for the secretion of mature cytokines, probably through the formation of pores in the plasma membrane during pyroptosis. Traditionally, inflammasomes have mainly been studied in professional immune cells of the innate immune system such as macrophages . However, recent studies show that Inflammasomkomponenten in various epithelial tissues expressed are, where they play an important role as a first line of defense. Inflammasomes be cytosolic by various types Pattern Recognition Receptors (PRRs) activated which various pathogen-associated molecular patterns (PAMPs), or risk-associated molecular pattern (DAMPS, engl. Danger associated molecular patterns detect). These PRRs include NLRs ( nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors ), AIM2 ( absent in melanoma 2 ), IFI16 ( IFN-inducible protein 16 ) and pyrin. (B&D) The various inflammasome receptors interact with the adapter protein ASC, which then recruits the inactive form of caspase- 1, pro-caspase-1, and activates it through proteolytic cleavage. The activated caspase can now catalyze the maturation of the pro-inflammatory cytokines IL-1β and IL-18 and cleave Gasdermin-D. In addition to these so-called canonical inflammasomes, the non-canonical inflammasome was also described, which is independent of caspase-1. Instead, cytosolic lipopolysaccharide is detected directly by another caspase (caspase-11 in mice, caspase-4 and 5 in human cells). Dysregulation of the inflammasome can lead to various diseases such as cancer , autoimmune diseases , metabolic and neurodegenerative diseases .
In addition, several rare mutations in humans have been described that affect the sensor molecules NLRP3 and NLRC4. The affected patients show a range of inflammation-related symptoms that can vary in severity.
NLRP1 inflammasome
NLRP1B in mice is activated in response to Bacillus anthracis lethal toxin. The toxin cleaves NLRP1b proteolytically, which leads to ubiquitination of the receptor and degradation in the proteasome . This degradation generates a C-terminal fragment which then binds to the rest of the protein so that a binding site for the formation of the multiprotein complex is exposed.
NLRP3 inflammasome
NLRP3 (or cryopyrin; encoded by NALP3) can be activated by a variety of stimuli. These include the DAMPs uric acid crystals , silicon dioxide crystals, titanium dioxide crystals , asbestos and the adjuvant aluminum hydroxide , as well as bacterial and viral PAMPs and toxins. The different stimuli converge in the end in a low intracellular potassium concentration as an activator for the NLRP3 inflammasome.
Hereditary diseases related to NLRP3
One of the proteins that make up the inflammasome is cryopyrin, or NALP3. A mutation in the CIAS1 gene , which codes for cryopyrin, leads to a congenital disease which, within the first few weeks of life, leads to an inflammatory systemic disease with fever , skin rash , joint damage primarily to the knee joints, hearing loss and intellectual disability due to chronic meningitis . This syndrome is called Inflammatory multisystem disease of the newborn ( Neonatal Onset Multisystem Inflammatory Disease referred NOMID). The lethality is 20%. Treatment with the interleukin-1 receptor antagonist anakinra leads to a significant improvement in symptoms and laboratory signs of inflammation in those affected .
Other congenital syndromes caused by mutations in CIAS1 are Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). Both syndromes have a milder course and are characterized by episodes with skin rash and systemic signs of inflammation, but there are no joint changes, chronic meningitis and intellectual disability.
NOMID, FCAS and MWS are assigned to the periodic fever syndromes .
Activation of the NLRP3 inflammasome by sodium urate crystals in patients with gout
Activation of the NLRP3 inflammasome by cholesterol or monosodium ureate crystals plays a role in inflammatory diseases such as arteriosclerosis and gout. The mechanism by which sodium urate crystals lower the intracellular potassium concentration after phagocytosis has long been unclear. In 2011, it was reported that endosomes containing sodium urate crystals fuse with acidic lysosomes. The low pH of the phagolysosomes causes a massive release of sodium and thus increases intracellular osmolarity. This is balanced by the passive supply of water through Aquaporine, which leads to swelling of the cells. This reduces the intracellular potassium concentration to values below the threshold value of 90 mM at which the NLRP3 inflammasome is activated. In vitro , the inhibitors of lysosomal acid formation ( ammonium chloride , chloroquine ) and the aquaporins ( mercury (II) chloride ; phloretin ) significantly reduced the production of IL-1β. Chloroquine can also be used in vivo as a pharmacological inhibitor of lysosomal acidification and significantly reduces IL-1β production. Consequently, chloroquine can be seen as a potential therapeutic for refractory gout. There is no approval for this application.
NAIP / NLRC4 inflammasome
In contrast to other inflammasome complexes, NLRC4 uses NAIPs ( NLR family apoptosis inhibitory proteins ) as receptors for PAMPs . NAIPs are activated by the binding of cytosolic bacterial PAMPs, namely components of the type 3 secretion system and flagellins , the molecular building block of the flagellum . After ligand binding, the NAIPs can interact with NLRC4 and initiate the formation of the multiprotein complex, which then recruits pro-caspase-1.
AIM2 inflammasome
The AIM2 inflammasome is a detector for cytosolic double-stranded DNA and plays an important role in the coordination of immune responses to viral and bacterial intracellular infections. AIM2 can also be activated by host cell DNA, which occurs in inflammatory diseases such as psoriasis .
IFI16 inflammasome
Similar to AIM2, IFI16 (IFN-inducible protein 16) is a DNA detector, but IFI16 is a DNA sensor in the cell nucleus and not in the cytosol. IFI16 in human cells, like the mouse ortholog IFI204, play an important role in the regulation of interferon production during bacterial and viral infections. For HIV infection , IFI16 has been shown to interact with viral DNA, activate caspase-1, and lead to cell death in CD4 + T cells.
Pyrine inflammasome
The formation of the pyrin inflammasome detects disturbances in the dynamics of the cytoskeleton , which are initiated by bacterial toxins and effector proteins. More precisely, the inactivation of the Rho-GTPase RHOA is detected by these bacterial factors.
The non-canonical inflammasome
The name “non-canonical inflammasome” comes from the fact that these inflammasome complexes act independently of caspase-1. In mice, caspase-11 is responsible for the non-canonical inflammasome, while the corresponding sensors in human cells are caspase-4 and caspase-5. All of these caspases bind intracellular LPS directly and then form the macromolecular complex for cleavage of Gasdermin-D. In addition, non-canonical inflammasomes can also indirectly activate the NLRP3 inflammasome, as potassium flows out of the cell through the membrane pores formed by Gasdermin-D. The NLRP3 inflammasome can then process the precursors of the proinflammatory cytokines and lead to the release of IL-1β and IL-18 in response to the activation of the non-canonical inflammasome.
Individual evidence
- ↑ a b c d e f g h i j k l m n o p q r Petr Broz, Vishva M. Dixit: Inflammasomes: mechanism of assembly, regulation and signaling . In: Nature Reviews Immunology . tape 16 , no. 7 , July 2016, ISSN 1474-1733 , p. 407-420 , doi : 10.1038 / nri.2016.58 .
- ^ A b c d e f Nathaniel Winsor, Christian Krustev, Jessica Bruce, Dana J. Philpott, Stephen E. Girardin: Canonical and noncanonical inflammasomes in intestinal epithelial cells . In: Cellular Microbiology . July 22, 2019, ISSN 1462-5814 , doi : 10.1111 / cmi.13079 .
- ↑ Neil Romberg, Tiphanie P. Vogel, Scott W. Canna: NLRC4 inflammasomopathies . In: Current Opinion in Allergy and Clinical Immunology . tape 17 , no. 6 , December 2017, ISSN 1473-6322 , p. 398-404 , doi : 10.1097 / ACI.0000000000000396 , PMID 28957823 .
- ↑ Beckley K. Davis, Haitao Wen, Jenny P.-Y. Ting: The Inflammasome NLRs in Immunity, Inflammation, and Associated Diseases . In: Annual Review of Immunology . tape 29 , no. 1 , April 23, 2011, ISSN 0732-0582 , p. 707-735 , doi : 10.1146 / annurev-immunol-031210-101405 , PMID 21219188 , PMC 4067317 (free full text).
- ↑ Shauna M. Crowley, Leigh A. Knodler, Bruce A. Vallance: Salmonella and the Inflammasome: Battle for Intracellular Dominance . In: Inflammasome Signaling and Bacterial Infections . tape 397 . Springer International Publishing, Cham 2016, ISBN 978-3-319-41170-5 , p. 43-67 , doi : 10.1007 / 978-3-319-41171-2_3 .
- ↑ Goldbach-Mansky R. et al .: Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition . In: New England Journal of Medicine . No. 355 , 2006, pp. 581-592 ( abstract ).
- ↑ C. Schorn, B. Frey et al. a .: Sodium overload and water influx activate the NALP3 inflammation. In: The Journal of biological chemistry. Volume 286, number 1, January 2011, pp. 35-41, doi: 10.1074 / jbc.M110.139048 , PMID 21051542 , PMC 3012992 (free full text).
- ↑ Hans-Jürgen Hettenkofer: Rheumatology. Georg Thieme Verlag, 2014, ISBN 978-3-13-175816-3 , p. 994 ( limited preview in Google book search).
- ↑ a b Yue Zhao, Feng Shao: The NAIP-NLRC4 inflammasome in innate immune detection of bacterial flagellin and type III secretion apparatus . In: Immunological Reviews . tape 265 , no. 1 , May 2015, p. 85-102 , doi : 10.1111 / imr.12293 .