• MeSH
• COVID-19 * imunologie   MeSH
• exprese genu imunologie   MeSH
• inflamasomy * imunologie   MeSH
• lidé MeSH
• makrofágy imunologie   MeSH
• protein S imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie MeSH

Rodina interleukinu 1 (IL-1) hraje zcela zásadní úlohu v procesech zánětu. Jako vůbec první popsaný cytokin je IL-1 velmi dobře prozkoumán a nyní zasazen do kontextu zánětlivých pochodů jak fyziologických, tak patologických. V přehledném článku jsou popsány základní mechanismy zánětu spojeného se zvýšením sekrece IL-1. Na straně patologické regulace zánětu jsou probrány autoinflamatorní stavy spojené s hyperaktivací IL-1, na což navazuje popis možností blokády IL-1 z hlediska diagnostiky a léčebných možností.

The IL-1 family of interleukin plays a crucial role in inflammation processes. As the first ever described cytokine, IL-1 is very well studied and now well placed in the context of inflammatory processes, both physiological and pathological associated with inflammatory diseases. The review article covers basic mechanisms of inflammation associated with an increase in IL-1 secretion. Pathological regulation of inflammation resulting in autoinflammatory conditions associated with hyper-activation of IL-1 are also discussed, together with an overview of the possibilities of IL-1 blockade.

• Klíčová slova
• anakinra, canakinumab,
• MeSH
• antagonista receptoru pro interleukin 1 aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• biologická terapie MeSH
• COVID-19 terapie   MeSH
• dědičné zánětlivé autoimunitní nemoci * farmakoterapie   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• inflamasomy imunologie   MeSH
• interleukin-1 * antagonisté a inhibitory   fyziologie   imunologie   MeSH
• lidé MeSH
• syndrom systémové zánětlivé reakce farmakoterapie   MeSH
• Check Tag
• lidé MeSH

Nanodiamonds (ND), especially fluorescent NDs, represent potentially applicable drug and probe carriers for in vitro/in vivo applications. The main purpose of this study was to relate physical-chemical properties of carboxylated NDs to their intracellular distribution and impact on membranes and cell immunity-activation of inflammasome in the in vitro THP-1 cell line model. Dynamic light scattering, nanoparticle tracking analysis, and microscopic methods were used to characterize ND particles and their intracellular distribution. Fluorescent NDs penetrated the cell membranes by both macropinocytosis and mechanical cutting through cell membranes. We proved accumulation of fluorescent NDs in lysosomes. In this case, lysosomes were destabilized and cathepsin B was released into the cytoplasm and triggered pathways leading to activation of inflammasome NLRP3, as detected in THP-1 cells. Activation of inflammasome by NDs represents an important event that could underlie the described toxicological effects in vivo induced by NDs. According to our knowledge, this is the first in vitro study demonstrating direct activation of inflammasome by NDs. These findings are important for understanding the mechanism(s) of action of ND complexes and explain the ambiguity of the existing toxicological data.

• MeSH
• buněčná membrána účinky léků   metabolismus   ultrastruktura   MeSH
• dynamický rozptyl světla MeSH
• elektronová mikroskopie MeSH
• fluorescence MeSH
• inflamasomy účinky léků   imunologie   metabolismus   MeSH
• intravitální mikroskopie metody   MeSH
• kathepsin B imunologie   metabolismus   MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• lyzozomy účinky léků   imunologie   metabolismus   ultrastruktura   MeSH
• mikroskopie atomárních sil MeSH
• nanodiamanty aplikace a dávkování   chemie   MeSH
• pinocytóza MeSH
• protein NLRP3 imunologie   metabolismus   MeSH
• THP-1 buňky MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The inhibitor of apoptosis proteins (IAPs) are best known for their ability to regulate cell survival and death processes. However, in addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division. Many of these IAP functions are non-redundant even though they are based on the same molecular mechanism of action. These distinct functions of IAPs derive from their capacity to target specific substrates for ubiquitination and/or proteolytic cleavage. The unique functions of IAPs also derives from their unique cellular localizations, cell type and tissue-specific expression patterns. The diverse roles of IAPs are reflected by the fact that in humans the IAP family comprises eight distinct members. Genetic evidence from human pathologies also attests to the non-redundant functions of the IAPs since very diverse diseases arise upon aberrant IAP expression. In this review, we give an overview of the known mechanisms of action of the various IAPs, and focus on their specific roles in mediating innate immunity. We also look at the distinct phenotypes related to the dysregulation of the IAPs, and the human pathologies associated with each human IAP.

• MeSH
• autoimunitní nemoci imunologie   patologie   MeSH
• buněčná smrt MeSH
• infekce imunologie   patologie   MeSH
• inflamasomy imunologie   MeSH
• inhibitory apoptózy genetika   imunologie   MeSH
• lidé MeSH
• signální transdukce MeSH
• viabilita buněk * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.

• MeSH
• Anaplasma phagocytophilum imunologie   MeSH
• dinoproston imunologie   MeSH
• ehrlichióza imunologie   MeSH
• ELISA MeSH
• imunoblotting MeSH
• inflamasomy imunologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• proteiny regulující apoptózu imunologie   MeSH
• proteiny vázající vápník imunologie   MeSH
• receptory prostaglandinů E - podtyp EP3 imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Tick saliva contains a number of effector molecules that inhibit host immunity and facilitate pathogen transmission. How tick proteins regulate immune signaling, however, is incompletely understood. Here, we describe that loop 2 of sialostatin L2, an anti-inflammatory tick protein, binds to annexin A2 and impairs the formation of the NLRC4 inflammasome during infection with the rickettsial agent Anaplasma phagocytophilum Macrophages deficient in annexin A2 secreted significantly smaller amounts of interleukin-1β (IL-1β) and IL-18 and had a defect in NLRC4 inflammasome oligomerization and caspase-1 activation. Accordingly, Annexin a2-deficient mice were more susceptible to A. phagocytophilum infection and showed splenomegaly, thrombocytopenia, and monocytopenia. Providing translational support to our findings, better binding of annexin A2 to sialostatin L2 in sera from 21 out of 23 infected patients than in sera from control individuals was also demonstrated. Overall, we establish a unique mode of inflammasome evasion by a pathogen, centered on a blood-feeding arthropod.

• MeSH
• Anaplasma phagocytophilum genetika   imunologie   MeSH
• annexin A2 chemie   genetika   imunologie   MeSH
• arachnida jako vektory chemie   genetika   imunologie   MeSH
• cystatiny chemie   genetika   imunologie   MeSH
• ehrlichióza imunologie   mikrobiologie   patologie   MeSH
• Escherichia coli genetika   metabolismus   MeSH
• imunitní únik * MeSH
• inflamasomy genetika   imunologie   MeSH
• interleukin-18 genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• kaspasa 1 genetika   imunologie   MeSH
• kaspasy genetika   imunologie   MeSH
• klíště chemie   genetika   imunologie   MeSH
• lidé MeSH
• makrofágy imunologie   mikrobiologie   MeSH
• molekulární modely MeSH
• myši MeSH
• protein - isoformy chemie   genetika   imunologie   MeSH
• proteiny regulující apoptózu chemie   genetika   imunologie   MeSH
• proteiny vázající vápník chemie   genetika   imunologie   MeSH
• regulace genové exprese MeSH
• rekombinantní proteiny chemie   genetika   imunologie   MeSH
• sekvence aminokyselin MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Autoinflamatorní syndromy představují relativně novou heterogenní skupinu familiárních či sporadických chorob klinicky charakterizovaných opakujícími se epizodami zánětlivých změn souvisejících většinou s nadměrnou aktivací dráhy interleukinu-1β. Projevují se většinou již v dětství, a to zejména kožními změnami, periodickými horečkami a kloubním postižením. S postupujícím vývojem poznání se jejich imunopatogenetické mechanismy průběžně odhalují a současně se ukazuje, že i běžné dermatózy mohou mít autoinflamatorní rysy. Rozpoznání úlohy inflamasomů a klíčových prozánětlivých mediátorů vrozeného imunitního systému v patogenezi těchto nemocí rozšiřuje možnosti nové cílené léčby.

The autoinflammatory syndromes represent a newly classified heterogenous subset of familiar or sporadic diseases, that are characterized by seemingly unprovoked episodes of inflammation due to excessive interleukin-1β activation. They manifest mainly in childhood with skin lesions, recurrent attacks of fever and joint symptoms. Their immunopathogenic mechanisms are gradually being revealed due to increasing level of knowledge and it appears that even common dermatoses might have present autoinflammatory signs. Recognition of the pathogenetic role of inflammasomes and key mediators of innate immune system opens the possibility for new targeted therapies.

• MeSH
• biologická terapie MeSH
• dědičné zánětlivé autoimunitní nemoci * etiologie   farmakoterapie   patofyziologie   MeSH
• familiární středomořská horečka farmakoterapie   patofyziologie   MeSH
• inflamasomy imunologie   MeSH
• interleukin-1 imunologie   MeSH
• juvenilní artritida patofyziologie   MeSH
• kožní nemoci * etiologie   farmakoterapie   patofyziologie   MeSH
• lidé MeSH
• mutace MeSH
• nedostatek mevalonátkinázy farmakoterapie   patofyziologie   MeSH
• periodické syndromy asociované s kryopyrinem farmakoterapie   patofyziologie   MeSH
• pyoderma gangrenosum patofyziologie   MeSH
• Stillova nemoc dospělých patofyziologie   MeSH
• syndrom Schnitzlerové farmakoterapie   patofyziologie   MeSH
• syndrom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Celiac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy. IL-1 cytokine family members IL-1β and IL-18 have been associated with the inflammatory conditions in CD patients. However, the mechanisms of IL-1 molecule activation in CD have not yet been elucidated. We show in this study that peripheral blood mononuclear cells (PBMC) and monocytes from celiac patients responded to pepsin digest of wheat gliadin fraction (PDWGF) by a robust secretion of IL-1β and IL-1α and a slightly elevated production of IL-18. The analysis of the upstream mechanisms underlying PDWGF-induced IL-1β production in celiac PBMC show that PDWGF-induced de novo pro-IL-1β synthesis, followed by a caspase-1 dependent processing and the secretion of mature IL-1β. This was promoted by K+ efflux and oxidative stress, and was independent of P2X7 receptor signaling. The PDWGF-induced IL-1β release was dependent on Nod-like receptor family containing pyrin domain 3 (NLRP3) and apoptosis-associated speck like protein (ASC) as shown by stimulation of bone marrow derived dendritic cells (BMDC) from NLRP3(-/-) and ASC(-/-) knockout mice. Moreover, treatment of human PBMC as well as MyD88(-/-) and Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)(-/-) BMDC illustrated that prior to the activation of caspase-1, the PDWGF-triggered signal constitutes the activation of the MyD88/TRIF/MAPK/NF-κB pathway. Moreover, our results indicate that the combined action of TLR2 and TLR4 may be required for optimal induction of IL-1β in response to PDWGF. Thus, innate immune pathways, such as TLR2/4/MyD88/TRIF/MAPK/NF-κB and an NLRP3 inflammasome activation are involved in wheat proteins signaling and may play an important role in the pathogenesis of CD.

• MeSH
• adaptorové proteiny vezikulární transportní genetika   imunologie   MeSH
• celiakie MeSH
• dospělí MeSH
• gliadin chemie   imunologie   MeSH
• inflamasomy účinky léků   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• leukocyty mononukleární účinky léků   imunologie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   imunologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• pepsin A MeSH
• peptidové fragmenty farmakologie   MeSH
• primární buněčná kultura MeSH
• protein MyD88 genetika   imunologie   MeSH
• regulace genové exprese účinky léků   imunologie   MeSH
• signální transdukce účinky léků   genetika   imunologie   MeSH
• toll-like receptor 2 genetika   imunologie   MeSH
• toll-like receptor 4 genetika   imunologie   MeSH
• transportní proteiny genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH