Abstract 447: β-cyclodextrin Reduces Cholesterol Crystal-induced Inflammation Through Modulating Complement Activation

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Terje Espevik ◽  
Siril S Bakke ◽  
Nathalie Niyonzima ◽  
Jan K Damås ◽  
Liv Ryan ◽  
...  
Keyword(s):  
Complement Activation ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Inflammasome Activation ◽  
Potential Candidate ◽  
Strong Inhibitor ◽  
Peripheral Blood Mononuclear ◽  
Inflammatory Cytokine Response ◽  
Complement Receptor 3 ◽  
Cholesterol Solubility

Atherosclerosis is an inflammatory condition and the underlying cause for cardiovascular disease. Cholesterol crystals (CC) are found to be abundant in atherosclerotic plaques and we have previously shown that CC initiate an inflammatory response via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances and is commonly used in pharmaceuticals or drug delivery. BCD is reported to increase cholesterol solubility and to promote the removal of cholesterol from foam cells. However, it remains unknown whether BCD has any effect on crystalline cholesterol. We here show that BCD attenuates the CC -induced inflammatory cytokine response as well as regulates a range of CC-related genes in human peripheral blood mononuclear cells. BCD binds to CC and prevents deposition of complement factors on CC in human plasma. Furthermore, BCD also decreases the formation of soluble terminal complement complex (TCC) and the expression of complement receptor 3 in response to CC stimulation in human whole blood. Induction of TCC by mono sodium urate crystals or zymosan was not affected by BCD. Of interest, after 1 hr of incubation, BCD is starting to dissolve the CC. These data demonstrate that BCD is a strong inhibitor of CC-induced inflammation, which might be explained by BCD-mediated attenuation of complement activation. These data suggest that BCD is a potential candidate for treatment of atherosclerosis.

scholarly journals Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

2016 ◽  
Vol 113 (50) ◽  
pp. 14384-14389 ◽  
Author(s):  
Hanne Van Gorp ◽  
Pedro H. V. Saavedra ◽  
Nathalia M. de Vasconcelos ◽  
Nina Van Opdenbosch ◽  
Lieselotte Vande Walle ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Autoinflammatory Disease ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Microtubule Assembly ◽  
Inflammasome Activation ◽  
Wild Type ◽  
Peripheral Blood Mononuclear ◽  
Mouse Macrophages ◽  
Mediterranean Fever

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.

scholarly journals SFTSV Infection Induced Interleukin-1β Secretion Through NLRP3 Inflammasome Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jian-Wei Liu ◽  
Min Chu ◽  
Yong-jun Jiao ◽  
Chuan-Min Zhou ◽  
Rui Qi ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Hemorrhagic Fever ◽  
Interleukin 1Β ◽  
Inflammasome Activation ◽  
Peripheral Blood Mononuclear ◽  
Nlrp3 Inflammasome Activation ◽  
Novel Drugs ◽  
Domain 3

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus that causes hemorrhagic fever. Previous studies showed that SFTSV-infected patients exhibited elevated levels of pro-inflammatory cytokines like interleukin-1β (IL-1β), indicating that SFTSV infection may activate inflammasomes. However, the detailed mechanism remains poorly understood. Herein, we found that SFTSV could stimulate the IL-1β secretion in the infected human peripheral blood mononuclear cells (PBMCs), human macrophages, and C57/BL6 mice. We demonstrate that the maturation and secretion of IL-1β during SFTSV infection is mediated by the nucleotide and oligomerization domain, leucine-rich repeat-containing protein family, pyrin-containing domain 3 (NLRP3) inflammasome. This process is dependent on protease caspase-1, a component of the NLRP3 inflammasome complex. For the first time, our study discovered the role of NLRP3 in response to SFTSV infection. This finding may lead to the development of novel drugs to impede the pathogenesis of SFTSV infection.

scholarly journals Mechanisms of Inflammasome Activation by Vibrio cholerae Secreted Toxins Vary with Strain Biotype

2015 ◽  
Vol 83 (6) ◽  
pp. 2496-2506 ◽  
Author(s):  
Jessica Queen ◽  
Shivani Agarwal ◽  
Jazel S. Dolores ◽  
Christian Stehlik ◽  
Karla J. F. Satchell
Keyword(s):  
Vibrio Cholerae ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Inflammasome Activation ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Peripheral Blood Mononuclear ◽  
Content Type ◽  
Murine Macrophages ◽  
El Tor

Activation of inflammasomes is an important aspect of innate immune responses to bacterial infection. Recent studies have linkedVibrio choleraesecreted toxins to inflammasome activation by using murine macrophages. To increase relevance to human infection, studies of inflammasome-dependent cytokine secretion were conducted with the human THP-1 monocytic cell line and corroborated in primary human peripheral blood mononuclear cells (PBMCs). Both El Tor and classical strains ofV. choleraeactivated ASC (apoptosis-associated speck-like protein-containing a CARD domain)-dependent release of interleukin-1β (IL-1β) when cultured with human THP-1 cells, but the pattern of induction was distinct, depending on the repertoire of toxins the strains produced. El Tor biotype strains induced release of IL-1β dependent on NOD-like receptor family pyrin domain-containing 3 (NLRP3) and ASC due to the secreted pore-forming toxin hemolysin. Unlike in studies with mouse macrophages, the MARTX toxin did not contribute to IL-1β release from human monocytic cells. Classical biotype strains, which do not produce either hemolysin or the MARTX toxin, activated low-level IL-1β release that was induced by cholera toxin (CT) and dependent on ASC but independent of NLRP3 and pyroptosis. El Tor strains likewise showed increased IL-1β production dependent on CT when the hemolysin gene was deleted. In contrast to studies with murine macrophages, this phenotype was dependent on a catalytically active CT A subunit capable of inducing production of cyclic AMP and not on the B subunit. These studies demonstrate that the induction of the inflammasome in human THP-1 monocytes and in PBMCs byV. choleraevaries with the biotype and is mediated by both NLRP3-dependent and -independent pathways.

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