scholarly journals Deep-sea microbes as tools to refine the rules of innate immune pattern recognition

2021 ◽  
Vol 6 (57) ◽  
pp. eabe0531
Author(s):  
Anna E. Gauthier ◽  
Courtney E. Chandler ◽  
Valentina Poli ◽  
Francesca M. Gardner ◽  
Aranteiti Tekiau ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Deep Sea ◽  
Mammalian Cells ◽  
Inflammatory Responses ◽  
Acyl Chain ◽  
Innate Immune ◽  
Bacterial Detection ◽  
Acyl Chain Length ◽  
Deep Sea Bacteria ◽  
Potential Determinant

The assumption of near-universal bacterial detection by pattern recognition receptors is a foundation of immunology. The limits of this pattern recognition concept, however, remain undefined. As a test of this hypothesis, we determined whether mammalian cells can recognize bacteria that they have never had the natural opportunity to encounter. These bacteria were cultivated from the deep Pacific Ocean, where the genus Moritella was identified as a common constituent of the culturable microbiota. Most deep-sea bacteria contained cell wall lipopolysaccharide (LPS) structures that were expected to be immunostimulatory, and some deep-sea bacteria activated inflammatory responses from mammalian LPS receptors. However, LPS receptors were unable to detect 80% of deep-sea bacteria examined, with LPS acyl chain length being identified as a potential determinant of immunosilence. The inability of immune receptors to detect most bacteria from a different ecosystem suggests that pattern recognition strategies may be defined locally, not globally.

scholarly journals Diverse Functions of Pulmonary Collectins in Host Defense of the Lung

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Shigeru Ariki ◽  
Chiaki Nishitani ◽  
Yoshio Kuroki
Keyword(s):  
Pattern Recognition ◽  
Growth Inhibition ◽  
Host Defense ◽  
Pulmonary Surfactant ◽  
Inflammatory Responses ◽  
Biological Activities ◽  
Innate Immune ◽  
The Other ◽  
Surfactant Proteins ◽  
Specific Proteins

Pulmonary surfactant is a mixture of lipids and proteins that covers alveolar surfaces and keeps alveoli from collapsing. Four specific proteins have been identified in surfactant. Among them, two C-type lectins, surfactant proteins A and D (SP-A and SP-D), are known to be implicated in host defense and regulation of inflammatory responses of the lung. These host defense lectins are structurally characterized by N-terminal collagen-like domains and lectin domains and are called pulmonary collectins. They prevent dissemination of infectious microbes by their biological activities including agglutination and growth inhibition. They also promote clearance of microbes by enhancing phagocytosis in macrophages. In addition, they interact with the other pattern-recognition molecules, including Toll-like receptors (TLRs) and TLR-associated molecules, CD14 and MD-2, and regulate inflammatory responses. Furthermore, recent studies have demonstrated that these collectins modulate functions of neutrophil-derived innate immune molecules by interacting with them. These findings indicate that pulmonary collectins play critical roles in host defense of the lung.

scholarly journals Human TLR4 and noncanonical inflammasome differ in their ability to respond to distinct lipid A variants

2021 ◽  
Author(s):  
Jasmine Alexander-Floyd ◽  
Antonia R. Bass ◽  
Erin M. Harberts ◽  
Daniel Grubaugh ◽  
Joseph D. Buxbaum ◽  
...  
Keyword(s):  
Lipid A ◽  
Inflammatory Responses ◽  
Bacterial Species ◽  
Acyl Chain ◽  
Innate Immune ◽  
Core Oligosaccharide ◽  
Phosphorylation State ◽  
Tlr4 Activation ◽  
Bacterial Lipid ◽  
Immune Detection

Detection of Gram-negative bacterial lipid A by the extracellular sensor, MD-2/TLR4 or the intracellular inflammasome sensors, CASP4 and CASP5, induces robust inflammatory responses. The chemical structure of lipid A, specifically the phosphorylation and acylation state, varies across and within bacterial species, potentially allowing pathogens to evade or suppress host immunity. Currently, it is not clear how distinct alterations in the phosphorylation or acylation state of lipid A affect both human TLR4 and CASP4/5 activation. Using a panel of engineered lipooligosaccharides (LOS) derived from Yersinia pestis with defined lipid A structures that vary in their acylation or phosphorylation state, we identified that differences in phosphorylation state did not affect TLR4 or CASP4/5 activation. However, the acylation state differentially impacted TLR4 and CASP4/5 activation. Specifically, all of the examined tetra-, penta-, and hexa-acylated LOS variants activated CASP4/5-dependent responses, whereas TLR4 responded to penta- and hexa-acylated LOS but did not respond to tetra-acylated LOS or penta-acylated LOS lacking the secondary acyl chain at the 3' position. As expected, lipid A alone was sufficient for TLR4 activation; however, human macrophages required both lipid A and the core oligosaccharide to mount a robust CASP4/5 inflammasome response. Our findings show that human TLR4 and CASP4/5 detect both shared and non-overlapping LOS/lipid A structures, which enables the innate immune system to recognize a wider range of bacterial LOS/lipid A, thereby constraining the ability of pathogens to evade innate immune detection.

scholarly journals The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Lixiang Sun ◽  
Wenjie Liu ◽  
Ling-juan Zhang
Keyword(s):  
Atopic Dermatitis ◽  
Human Body ◽  
Lupus Erythematosus ◽  
Mammalian Cells ◽  
Skin Diseases ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Host Responses ◽  
Molecular Patterns

As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.

scholarly journals Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Kathleen L. McCoy
Keyword(s):  
Pattern Recognition ◽  
Immune Cells ◽  
Innate Immune System ◽  
Cannabinoid Receptors ◽  
Inflammatory Responses ◽  
Endocannabinoid System ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Toll Like Receptor ◽  
Receptor Family

Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents. Abundant evidence indicates that cannabinoids modulate immune responses. An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors. Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells. Cannabinoids suppress Toll-like receptor-mediated inflammatory responses. However, the relationship between the endocannabinoid system and innate immune system may not be one-sided. Innate immune cells express cannabinoid receptors and produce endogenous cannabinoids. Hence, innate immune cells may play a role in regulating endocannabinoid homeostasis, and, in turn, the endocannabinoid system modulates local inflammatory responses. Studies designed to probe the interaction between the innate immune system and the endocannabinoid system may identify new potential molecular targets in developing therapeutic strategies for chronic inflammatory diseases. This review discusses the endocannabinoid system and Toll-like receptor family and evaluates the interaction between them.

scholarly journals Differential recognition of HIV-stimulated IL-1β and IL-18 secretion through NLR and NAIP signalling in monocyte-derived macrophages

2021 ◽  
Vol 17 (4) ◽  
pp. e1009417
Author(s):  
Kathy Triantafilou ◽  
Christopher J. K. Ward ◽  
Magdalena Czubala ◽  
Robert G. Ferris ◽  
Emma Koppe ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Inflammatory Responses ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Inflammatory Cytokine Production ◽  
Protein Gp41 ◽  
One Step ◽  
Hiv Envelope ◽  
Hiv 1

Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus in the later phases of the infection is often predominantly macrophage-tropic and this tropism contributes to a chronic inflammatory and immune activation state that is observed in HIV patients. Pattern recognition receptors of the innate immune system are the key molecules that recognise HIV and mount the inflammatory responses in macrophages. The innate immune response against HIV-1 is potent and elicits caspase-1-dependent pro-inflammatory cytokine production of IL-1β and IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating this response little is known about the pattern recognition receptors that trigger the “priming” signal for inflammasome activation, the NLRs involved or the HIV components that trigger the response. Using a combination of siRNA knockdowns in monocyte derived macrophages (MDMs) of different TLRs and NLRs as well as chemical inhibition, it was demonstrated that HIV Vpu could trigger inflammasome activation via TLR4/NLRP3 leading to IL-1β/IL-18 secretion. The priming signal is triggered via TLR4, whereas the activation signal is triggered by direct effects on Kv1.3 channels, causing K+ efflux. In contrast, HIV gp41 could trigger IL-18 production via NAIP/NLRC4, independently of priming, as a one-step inflammasome activation. NAIP binds directly to the cytoplasmic tail of HIV envelope protein gp41 and represents the first non-bacterial ligand for the NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets to resolve specific inflammatory pathologies associated with HIV-1 infection in macrophages.

scholarly journals Phospholipid exchange shows insulin receptor activity is supported by both the propensity to form wide bilayers and ordered domains (rafts)

2021 ◽  
Author(s):  
Pavana Suresh ◽  
W. Todd Miller ◽  
Erwin London
Keyword(s):  
Insulin Receptor ◽  
Chain Length ◽  
Mammalian Cells ◽  
Plasma Membranes ◽  
Acyl Chain ◽  
Phospholipid Composition ◽  
Domain Formation ◽  
Lipid Structure ◽  
Acyl Chain Length ◽  
Lipid Exchange

ABSTRACTUsing efficient methyl-alpha-cyclodextrin mediated lipid exchange, we studied the effect of altering plasma membrane outer leaflet phospholipid composition upon the activity of insulin receptor (IR) in mammalian cells. After substitution of endogenous lipids with lipids having an ability to form liquid ordered (Lo) domains (sphingomyelins) or liquid disordered (Ld) domains (unsaturated phosphatidylcholines (PCs)), we found that the propensity of lipids to form ordered domains is required for high IR activity. Additional substitution experiments using a series of saturated PCs showed that IR activity increased substantially with increasing acyl chain length. Increasing acyl chain length increases both bilayer width and the propensity to form ordered domains. To distinguish the effects of membrane width and domain formation, we incorporated purified IR into alkyl maltoside micelles with increasing hydrocarbon lengths. IR activity increases with increased chain length, but more modestly than by increasing lipid acyl chain length in cells. This suggests that the ability to form Lo domains as well as wide bilayer width contributes to increased IR activity. Inhibition of phosphatases with sodium orthovanadate showed that some of the lipid dependence of IR activity upon lipid structure reflected protection from phosphatases by lipids that support Lo domain formation. The results are consistent with a model in which a combination of bilayer width and ordered domain formation modulate IR activity via effects upon IR conformation and accessibility to phosphatases.SignificanceThis study shows how methyl-α-cyclodextrin mediated lipid exchange can be used to probe the influence of lipid structure upon the functioning of a transmembrane receptor. Plasma membranes having a propensity to form Lo domains are required to support a high level of IR activity. The studies indicate this may reflect an effect of lipid environment upon IR domain localization, which in turn alters its conformation and vulnerability to phosphatases. Alterations in lipid composition could conceivably regulate IR activity in vivo.

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