scholarly journals Native and oxidised lipoproteins negatively regulate the serum amyloid A‐induced NLRP3 inflammasome activation in human macrophages

2021 ◽  
Vol 10 (8) ◽  
Author(s):  
Katariina Nurmi ◽  
Katri Niemi ◽  
Ilona Kareinen ◽  
Kristiina Silventoinen ◽  
Martina B Lorey ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Inflammasome Activation ◽  
Human Macrophages ◽  
Amyloid A ◽  
Nlrp3 Inflammasome Activation

scholarly journals Mycobacterium tuberculosis Binds Human Serum Amyloid A and the Interaction Modulates the Colonization of Human Macrophages and the Transcriptional Response of the Pathogen

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1264
Author(s):  
Malwina Kawka ◽  
Anna Brzostek ◽  
Katarzyna Dzitko ◽  
Jakub Kryczka ◽  
Radosław Bednarek ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Serum Amyloid A ◽  
Acute Phase Protein ◽  
Transcriptional Response ◽  
Serum Amyloid ◽  
Host Protein ◽  
Binding Interaction ◽  
Human Macrophages ◽  
Amyloid A ◽  
Transporter Systems

As a very successful pathogen with outstanding adaptive properties, Mycobacterium tuberculosis (Mtb) has developed a plethora of sophisticated mechanisms to subvert host defenses and effectively enter and replicate in the harmful environment inside professional phagocytes, namely, macrophages. Here, we demonstrated the binding interaction of Mtb with a major human acute phase protein, namely, serum amyloid A (SAA1), and identified AtpA (Rv1308), ABC (Rv2477c), EspB (Rv3881c), TB 18.6 (Rv2140c), and ThiC (Rv0423c) membrane proteins as mycobacterial effectors responsible for the pathogen-host protein interplay. SAA1-opsonization of Mtb prior to the infection of human macrophages favored bacterial entry into target phagocytes accompanied by a substantial increase in the load of intracellularly multiplying and surviving bacteria. Furthermore, binding of human SAA1 by Mtb resulted in the up- or downregulation of the transcriptional response of tubercle bacilli. The most substantial changes were related to the increased expression level of the genes of two operons encoding mycobacterial transporter systems, namely, mmpL5/mmpS5 (rv0676c), and rv1217c, rv1218c. Therefore, we postulate that during infection, Mtb-SAA1 binding promotes the infection of host macrophages by tubercle bacilli and modulates the functional response of the pathogen.

scholarly journals Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ines Diaz-del-Olmo ◽  
Jonathan Worboys ◽  
Fatima Martin-Sanchez ◽  
Anna Gritsenko ◽  
Ashley R. Ambrose ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Pore Formation ◽  
Membrane Attack Complex ◽  
Inflammasome Activation ◽  
Adapter Protein ◽  
Human Macrophages ◽  
Danger Signals ◽  
Nlrp3 Inflammasome Activation ◽  
Golgi Network ◽  
Stimulation Of

Interleukin 1β (IL-1β) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1β release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1β release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1β release in human macrophages.

scholarly journals β-Glucan–induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies

2020 ◽  
Vol 130 (9) ◽  
pp. 4561-4573 ◽  
Author(s):  
Giorgio Camilli ◽  
Mathieu Bohm ◽  
Alícia Corbellini Piffer ◽  
Rachel Lavenir ◽  
David L. Williams ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Human Macrophages ◽  
Nlrp3 Inflammasome Activation

scholarly journals Serum Amyloid A Activates the NLRP3 Inflammasome and Promotes Th17 Allergic Asthma in Mice

2011 ◽  
Vol 187 (1) ◽  
pp. 64-73 ◽  
Author(s):  
Jennifer L. Ather ◽  
Karina Ckless ◽  
Rebecca Martin ◽  
Kathryn L. Foley ◽  
Benjamin T. Suratt ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Nlrp3 Inflammasome ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid A

scholarly journals Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

2011 ◽  
Vol 186 (11) ◽  
pp. 6119-6128 ◽  
Author(s):  
Katri Niemi ◽  
Laura Teirilä ◽  
Jani Lappalainen ◽  
Kristiina Rajamäki ◽  
Marc H. Baumann ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cathepsin B ◽  
P2x7 Receptor ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amyloid A

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality

2021 ◽  
Author(s):  
Stefan J Schunk ◽  
Marcus E Kleber ◽  
Winfried März ◽  
Shichao Pang ◽  
Stephen Zewinger ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Systemic Inflammation ◽  
Cardiovascular Mortality ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Amyloid A ◽  
Nlrp3 Inflammasome Activation ◽  
Artery Disease ◽  
Genetically Determined

Abstract Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

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