scholarly journals Cytosolic Sensor of Bacterial Lipopolysaccharide in Human Macrophages

2021 ◽  
Author(s):  
Maricarmen Rojas-Lopez ◽  
Amanda S. Zajac ◽  
Thomas E. Wood ◽  
Kelly A. Miller ◽  
Maria Luisa Gil Marques ◽  
...  
Keyword(s):  
Canonical Pathway ◽  
Innate Immune ◽  
Bacterial Lipopolysaccharide ◽  
Inflammasome Activation ◽  
Innate Immune Responses ◽  
Human Macrophages ◽  
Pyrin Domain ◽  
Cell Cytosol ◽  
Major Mediator ◽  
Oligomerization Domain

Inflammasomes are cytosolic supramolecular organizing centers that, in response to pathogen-derived molecules and endogenous danger signals, assemble and activate innate immune responses. Bacterial lipopolysaccharide (LPS) is an inflammasome trigger and a major mediator of inflammation during infection, including during the potentially lethal condition sepsis. Activation of most inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein (NLRP) or other sensor protein that in turn activates a pro-inflammatory caspase. LPS that accesses the cell cytosol (cLPS) induces cell-autonomous activation of a non-canonical inflammasome that contains caspases-4/5 in humans or caspase-11 in mice1-3. Whereas the NLRPs that sense most pathogen triggers have been identified, no NLRP is known to sense cLPS, which together with the observation that caspases-4, -5, and -11 bind LPS in vitro4, has led to the postulate that inflammasome activation by cLPS occurs independent of an NLRP. Here we show that primate-specific NLRP11 senses cLPS and promotes the activation of caspase-4. We found that in response to infection by each of several gram-negative intracellular bacterial pathogens or to LPS transfection, efficient activation of the non-canonical pathway in human-derived macrophages depends on NLRP11. Further, we found that in both immortalized human-derived macrophages and primary human macrophages, the dependence of the non-canonical pathway on NLRP11 is due to detection of cLPS. Moreover, in cell lysates, NLRP11 binds LPS independently of caspase-4 and binds caspase-4 independently of LPS. Our results demonstrate that NLRP11 senses cLPS and promotes LPS-dependent activation of caspase-4. NLRP11 is a previously missing link in the human non-canonical inflammasome activation pathway. 

scholarly journals Upregulation of Nucleotide-Binding Oligomerization Domain-, LRR- and Pyrin Domain-Containing Protein 3 in Motoneurons Following Peripheral Nerve Injury in Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
Bernát Nógrádi ◽  
Ádám Nyúl-Tóth ◽  
Mihály Kozma ◽  
Kinga Molnár ◽  
Roland Patai ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Motor Neurons ◽  
Nucleotide Binding ◽  
Inflammasome Activation ◽  
Neuroprotective Effects ◽  
Pyrin Domain ◽  
Basal Expression ◽  
Wide Range ◽  
Treatment Paradigm ◽  
Oligomerization Domain

Neuronal injuries are accompanied by release and accumulation of damage-associated molecules, which in turn may contribute to activation of the immune system. Since a wide range of danger signals (including endogenous ones) are detected by the nucleotide-binding oligomerization domain-, LRR- and pyrin domain-containing protein 3 (NLRP3) pattern recognition receptor, we hypothesized that NLRP3 may become activated in response to motor neuron injury. Here we show that peripheral injury of the oculomotor and the hypoglossal nerves results in upregulation of NLRP3 in corresponding motor nuclei in the brainstem of mice. Although basal expression of NLRP3 was observed in microglia, astroglia and neurons as well, its upregulation and co-localization with apoptosis-associated speck-like protein containing a caspase activation and recruitment domain, suggesting inflammasome activation, was only detected in neurons. Consequently, increased production of active pro-inflammatory cytokines interleukin-1β and interleukin-18 were detected after hypoglossal nerve axotomy. Injury-sensitive hypoglossal neurons responded with a more pronounced NLRP3 upregulation than injury-resistant motor neurons of the oculomotor nucleus. We further demonstrated that the mitochondrial protector diazoxide was able to reduce NLRP3 upregulation in a post-operative treatment paradigm. Our results indicate that NLRP3 is activated in motoneurons following acute nerve injury. Blockade of NLRP3 activation might contribute to the previously observed anti-inflammatory and neuroprotective effects of diazoxide.

scholarly journals Activation of NLRP3 and AIM2 Inflammasomes by Porphyromonas gingivalis Infection

2013 ◽  
Vol 82 (1) ◽  
pp. 112-123 ◽  
Author(s):  
Eunjoo Park ◽  
Hee Sam Na ◽  
Yu-Ri Song ◽  
Seong Yeol Shin ◽  
You-Me Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Porphyromonas Gingivalis ◽  
Molecular Mechanisms ◽  
Atp Release ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Innate Immune Responses ◽  
Content Type ◽  
Periodontal Destruction ◽  
Tlr4 Activation

ABSTRACTPorphyromonas gingivalis, a major periodontopathogen, is involved in the pathogenesis of periodontitis. Interleukin-1β (IL-1β), a proinflammatory cytokine, regulates innate immune responses and is critical for the host defense against bacterial infection. However, excessive IL-1β is linked to periodontal destruction. IL-1β synthesis, maturation, and secretion are tightly regulated by Toll-like receptor (TLR) signaling and inflammasome activation. We found much higher levels of inflammasome components in the gingival tissues from patients with chronic periodontitis than in those from healthy controls. To investigate the molecular mechanisms by whichP. gingivalisinfection causes IL-1β secretion, we examined the characteristics ofP. gingivalis-induced signaling in differentiated THP-1 cells. We found thatP. gingivalisinduces IL-1β secretion and inflammatory cell death via caspase-1 activation. We also found thatP. gingivalis-induced IL-1β secretion and pyroptic cell death required both NLRP3 and AIM2 inflammasome activation. The activation of the NLRP3 inflammasome was mediated by ATP release, the P2X7receptor, and lysosomal damage. In addition, we found that the priming signal via TLR2 and TLR4 activation precedesP. gingivalis-induced IL-1β release. Our study provides novel insight into the innate immune response againstP. gingivalisinfection which could potentially be used for the prevention and therapy of periodontitis.

scholarly journals Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2

2019 ◽  
Vol 217 (3) ◽  
Author(s):  
José Luís Fachi ◽  
Cristiane Sécca ◽  
Patrícia Brito Rodrigues ◽  
Felipe Cézar Pinheiro de Mato ◽  
Blanda Di Luccia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Immune Responses ◽  
Pseudomembranous Colitis ◽  
Short Chain Fatty Acid ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Innate Immune Responses ◽  
Predisposing Factor ◽  
Free Fatty Acid Receptor ◽  
The Impact

Antibiotic-induced dysbiosis is a key predisposing factor for Clostridium difficile infections (CDIs), which cause intestinal disease ranging from mild diarrhea to pseudomembranous colitis. Here, we examined the impact of a microbiota-derived metabolite, short-chain fatty acid acetate, on an acute mouse model of CDI. We found that administration of acetate is remarkably beneficial in ameliorating disease. Mechanistically, we show that acetate enhances innate immune responses by acting on both neutrophils and ILC3s through its cognate receptor free fatty acid receptor 2 (FFAR2). In neutrophils, acetate-FFAR2 signaling accelerates their recruitment to the inflammatory sites, facilitates inflammasome activation, and promotes the release of IL-1β; in ILC3s, acetate-FFAR2 augments expression of the IL-1 receptor, which boosts IL-22 secretion in response to IL-1β. We conclude that microbiota-derived acetate promotes host innate responses to C. difficile through coordinate action on neutrophils and ILC3s.

scholarly journals NOD1-Mediated Mucosal Host Defense againstHelicobacter pylori

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Tomohiro Watanabe ◽  
Naoki Asano ◽  
Atsushi Kitani ◽  
Ivan J. Fuss ◽  
Tsutomu Chiba ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune Responses ◽  
Host Defense ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Gastric Epithelial Cells ◽  
Innate Immune Responses ◽  
Cytokines And Chemokines ◽  
H Pylori ◽  
Oligomerization Domain

Infection of the stomach withHelicobacter pyloriis an important risk factor for gastritis, peptic ulcer, and gastric carcinoma. Although it has been well established that persistent colonization byH. pyloriis associated with adaptive Th1 responses, the innate immune responses leading to these Th1 responses are poorly defined. Recent studies have shown that the activation of nucleotide-binding oligomerization domain 1 (NOD1) in gastric epithelial cells plays an important role in innate immune responses againstH. pylori. The detection ofH. pylori-derived ligands by cytosolic NOD1 induces several host defense factors, including antimicrobial peptides, cytokines, and chemokines. In this paper, we review the molecular mechanisms by which NOD1 contributes to mucosal host defense againstH. pyloriinfection of the stomach.

scholarly journals Mitochondria: powering the innate immune response to Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Kristin L. Patrick ◽  
Robert O. Watson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Bacterial Pathogen ◽  
Tuberculosis Patient ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Type I ◽  
Innate Immune Responses ◽  
Mycobacterium Tuberculosis Infection

Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for crosstalk or synergy between bacteria- and mitochondria-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking—and intriguing—in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages leading to metabolic changes and triggering potent innate immune responses. Research from our labs and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyper-activating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrial-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.

Mitochondrial DNA in innate immune responses against infectious diseases

2020 ◽  
Vol 48 (6) ◽  
pp. 2823-2838
Author(s):  
Palamou Das ◽  
Oishee Chakrabarti
Keyword(s):  
Immune Response ◽  
Mitochondrial Dna ◽  
Infectious Diseases ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Mitochondrial Dynamics ◽  
Innate Immune ◽  
Activation Mechanism ◽  
Inflammasome Activation ◽  
Innate Immune Responses

Mitochondrial DNA (mtDNA) can initiate an innate immune response when mislocalized in a compartment other than the mitochondrial matrix. mtDNA plays significant roles in regulating mitochondrial dynamics as well as mitochondrial unfolded protein response (UPR). The mislocalized extra-mtDNA can elicit innate immune response via cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) pathway, inducing the expression of the interferon-stimulated genes (ISGs). Also, cytosolic damaged mtDNA is cleared up by various pathways which are responsible for participating in the activation of inflammatory responses. Four pathways of extra-mitochondrial mtDNA clearance are highlighted in this review — the inflammasome activation mechanism, neutrophil extracellular traps formation, recognition by Toll-like receptor 9 and transfer of mtDNA between cells packaged into extracellular vesicles. Anomalies in these pathways are associated with various diseases. We posit our review in the present pandemic situation and discuss how mtDNA elicits innate immune responses against different viruses and bacteria. This review gives a comprehensive picture of the role of extra-mitochondrial mtDNA in infectious diseases and speculates that research towards its understanding would help establish its therapeutic potential.

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