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Lipopolysaccharide: Bacterial Endotoxin 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 20001

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Prof. Dr. Susana Merino Montero

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Department of Genetic, Microbiology and Statistic, University of Barcelona, 08028 Barcelona, Spain
Interests: lipopolysaccharide; genomics; proteomics
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Lipopolysaccharide (LPS) is the major molecular surface component of the outer membrane of Gram-negative bacteria. LPSs are negatively charged molecules exposed to the external environment and that provide a physical barrier that protects bacteria from antibacterial agents. They are amphiphilic molecules, consisting of a hydrophilic polysaccharide or oligosaccharide portion covalently linked to a hydrophobic and highly conserved lipid portion, termed lipid A, which is embedded in the external face of the outer membrane. The saccharide portion is diverse in terms of length and composition among different Gram-negative bacterial species, and can be divided in two domains: the core, which can be subdivided into inner and outer cores, and the O-antigen chain. The inner core is proximal to lipid A, which is required for bacterial viability, and contains unusual sugars, such as 3-deoxy-D-manno-octulosonic acid (Kdo) and heptoses. However, the outer core typically contains hexose sugars. The O-antigen chain is the most external domain, is highly variable, and is composed of repeating oligosaccharide units.

The LPS lipid A released from cell surfaces of bacteria during multiplication, lysis, or death can be recognized by specific host cell receptors and is responsible for the activation of the innate immune system via the induction of inflammatory cytokines release. The uncontrolled activation of the innate immune response triggers the development of septic shock and multiple-organ failure. Thus, lipid A is one of the most potent immune-stimulators, of which the toxicity depends on its primary structure and the severity of infection. Although lipid A is highly conserved biochemically, some bacteria show an impressive amount of diversity. Variations of lipid A serve to promote survival by providing resistance to components of the innate immune system and help to evade recognition by Toll-like receptors.

The set of articles proposed for this Special Issue will examine the structure, composition, biological activity, host interaction, and induction of the innate immunity of the Gram-negative bacterial endotoxin.

Prof. Susana Merino Montero
Guest Editor

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Keywords

lipid A
core LPS
O-antigen LPS
glycoconjugates
chemical structure
biological significance
host interaction
immune evasion

Published Papers (6 papers)

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Research

20 pages, 6135 KiB

Open AccessArticle

Uremia-Induced Gut Barrier Defect in 5/6 Nephrectomized Mice Is Worsened by Candida Administration through a Synergy of Uremic Toxin, Lipopolysaccharide, and (1➔3)-β-D-Glucan, but Is Attenuated by Lacticaseibacillus rhamnosus L34

by Somkanya Tungsanga, Wimonrat Panpetch, Thansita Bhunyakarnjanarat, Kanyarat Udompornpitak, Pisut Katavetin, Wiwat Chancharoenthana, Piraya Chatthanathon, Naraporn Somboonna, Kriang Tungsanga, Somying Tumwasorn and Asada Leelahavanichkul

Int. J. Mol. Sci. 2022, 23(5), 2511; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052511 - 24 Feb 2022

Cited by 19 | Viewed by 2610

Abstract

A chronic kidney disease (CKD) causes uremic toxin accumulation and gut dysbiosis, which further induces gut leakage and worsening CKD. Lipopolysaccharide (LPS) of Gram-negative bacteria and (1➔3)-β-D-glucan (BG) of fungi are the two most abundant gut microbial molecules. Due to limited data on the impact of intestinal fungi in CKD mouse models, the influences of gut fungi and Lacticaseibacillus rhamnosus L34 (L34) on CKD were investigated using oral C. albicans-administered 5/6 nephrectomy (5/6Nx) mice. At 16 weeks post-5/6Nx, Candida-5/6Nx mice demonstrated an increase in proteinuria, serum BG, serum cytokines (tumor necrotic factor-α; TNF-α and interleukin-6), alanine transaminase (ALT), and level of fecal dysbiosis (Proteobacteria on fecal microbiome) when compared to non-Candida-5/6Nx. However, serum creatinine, renal fibrosis, or gut barrier defect (FITC-dextran assay and endotoxemia) remained comparable between Candida- versus non-Candida-5/6Nx. The probiotics L34 attenuated several parameters in Candida-5/6Nx mice, including fecal dysbiosis (Proteobacteria and Bacteroides), gut leakage (fluorescein isothiocyanate (FITC)-dextran), gut-derived uremic toxin (trimethylamine-N-oxide; TMAO) and indoxyl sulfate; IS), cytokines, and ALT. In vitro, IS combined with LPS with or without BG enhanced the injury on Caco-2 enterocytes (transepithelial electrical resistance and FITC-dextran permeability) and bone marrow-derived macrophages (supernatant cytokines (TNF-α and interleukin-1 β; IL-1β) and inflammatory genes (TNF-α, IL-1β, aryl hydrocarbon receptor, and nuclear factor-κB)), compared with non-IS activation. These injuries were attenuated by the probiotics condition media. In conclusion, Candida administration worsens kidney damage in 5/6Nx mice through systemic inflammation, partly from gut dysbiosis-induced uremic toxins, which were attenuated by the probiotics. The additive effects on cell injury from uremic toxin (IS) and microbial molecules (LPS and BG) on enterocytes and macrophages might be an important underlying mechanism. Full article

(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)

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13 pages, 1564 KiB

Open AccessArticle

Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model

by Aleksandra Szczepkowska, Maciej Wójcik, Dorota Tomaszewska-Zaremba, Hanna Antushevich, Agata Krawczyńska, Wiktoria Wiechetek, Janina Skipor and Andrzej Przemysław Herman

Int. J. Mol. Sci. 2021, 22(24), 13237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413237 - 08 Dec 2021

Cited by 5 | Viewed by 2653

Abstract

This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin—lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1β) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges. Full article

(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)

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13 pages, 4169 KiB

Open AccessArticle

Nintedanib Regulates GRK2 and CXCR2 to Reduce Neutrophil Recruitment in Endotoxin-Induced Lung Injury

by Vincent Yi-Fong Su, Wei-Chih Chen, Wen-Kuang Yu, Huai-Hsuan Wu, Hao Chen and Kuang-Yao Yang

Int. J. Mol. Sci. 2021, 22(18), 9898; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189898 - 13 Sep 2021

Cited by 4 | Viewed by 5929

Abstract

The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsis-induced acute lung injury (ALI) remains unclear. Lipopolysaccharide (LPS), also known as endotoxin, has been used to induce ALI. The goal of this study was to assess the effect of nintedanib in attenuating the histopathological changes of LPS-induced ALI. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h and 10 min before intratracheal endotoxin instillation. Lung histopathological characteristics, adhesion molecule expression, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed after 24 h. We found that nintedanib significantly reduced histopathological changes and neutrophil recruitment in LPS-induced ALI. The number of neutrophils in bronchoalveolar lavage fluid (BALF) was reduced in nintedanib-treated relative to untreated mice with ALI. Nintedanib mediated the downregulation of the chemotactic response to LPS by reducing the expression of adhesion molecules and the phosphorylated p38:total p38 mitogen-activated protein kinase (MAPK) ratio in the lungs of mice with ALI. Nintedanib also reduced the expression of lymphocyte antigen 6 complex locus G6D (Ly6G) and very late antigen 4 (VLA-4) in BALF neutrophils and mediated the downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in mice with LPS-induced ALI. Nintedanib improved the histopathological changes of LPS-induced ALI by reducing neutrophil chemotaxis. These effects were mediated by the inhibition of adhesion molecules via the activation of GRK2 and the inhibition of p38 MAPK and CXCR2. Full article

(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)

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16 pages, 2098 KiB

Open AccessArticle

Bordetella Adenylate Cyclase Toxin Elicits Airway Mucin Secretion through Activation of the cAMP Response Element Binding Protein

by Anna Malandra, Waheed Ur Rahman, Nela Klimova, Gaia Streparola, Jana Holubova, Adriana Osickova, Simone Bariselli, Peter Sebo and Radim Osicka

Int. J. Mol. Sci. 2021, 22(16), 9064; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169064 - 23 Aug 2021

Cited by 3 | Viewed by 2466

Abstract

The mucus layer protects airway epithelia from damage by noxious agents. Intriguingly, Bordetella pertussis bacteria provoke massive mucus production by nasopharyngeal epithelia during the initial coryza-like catarrhal stage of human pertussis and the pathogen transmits in mucus-containing aerosol droplets expelled by sneezing and post-nasal drip-triggered cough. We investigated the role of the cAMP-elevating adenylate cyclase (CyaA) and pertussis (PT) toxins in the upregulation of mucin production in B. pertussis-infected airway epithelia. Using human pseudostratified airway epithelial cell layers cultured at air–liquid interface (ALI), we show that purified CyaA and PT toxins (100 ng/mL) can trigger production of the major airway mucins Muc5AC and Muc5B. Upregulation of mucin secretion involved activation of the cAMP response element binding protein (CREB) and was blocked by the 666-15-Calbiochem inhibitor of CREB-mediated gene transcription. Intriguingly, a B. pertussis mutant strain secreting only active PT and producing the enzymatically inactive CyaA-AC^– toxoid failed to trigger any important mucus production in infected epithelial cell layers in vitro or in vivo in the tracheal epithelia of intranasally infected mice. In contrast, the PT^– toxoid-producing B. pertussis mutant secreting the active CyaA toxin elicited a comparable mucin production as infection of epithelial cell layers or tracheal epithelia of infected mice by the wild-type B. pertussis secreting both PT and CyaA toxins. Hence, the cAMP-elevating activity of B. pertussis-secreted CyaA was alone sufficient for activation of mucin production through a CREB-dependent mechanism in B. pertussis-infected airway epithelia in vivo. Full article

(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)

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22 pages, 5620 KiB

Open AccessArticle

Candida Administration in Bilateral Nephrectomy Mice Elevates Serum (1→3)-β-D-glucan That Enhances Systemic Inflammation Through Energy Augmentation in Macrophages

by Jiraphorn Issara-Amphorn, Cong Phi Dang, Wilasinee Saisorn, Kavee Limbutara and Asada Leelahavanichkul

Int. J. Mol. Sci. 2021, 22(9), 5031; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22095031 - 10 May 2021

Cited by 23 | Viewed by 2348

Abstract

Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia. Full article

(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)

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22 pages, 6000 KiB

Open AccessArticle

Lipopolysaccharide-Enhanced Responses against Aryl Hydrocarbon Receptor in FcgRIIb-Deficient Macrophages, a Profound Impact of an Environmental Toxin on a Lupus-Like Mouse Model

by Kanyarat Udompornpitak, Thansita Bhunyakarnjanarat, Awirut Charoensappakit, Cong Phi Dang, Wilasinee Saisorn and Asada Leelahavanichkul

Int. J. Mol. Sci. 2021, 22(8), 4199; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084199 - 18 Apr 2021

Cited by 14 | Viewed by 2556

Abstract

Fc gamma receptor IIb (FcgRIIb) is the only inhibitory-FcgR in the FcgR family, and FcgRIIb-deficient (FcgRIIb^−/−) mice develop a lupus-like condition with hyper-responsiveness against several stimulations. The activation of aryl hydrocarbon receptor (Ahr), a cellular environmental sensor, might aggravate activity of the lupus-like condition. As such, 1,4-chrysenequinone (1,4-CQ), an Ahr-activator, alone did not induce supernatant cytokines from macrophages, while the 24 h pre-treatment by lipopolysaccharide (LPS), a representative inflammatory activator, prior to 1,4-CQ activation (LPS/1,4-CQ) predominantly induced macrophage pro-inflammatory responses. Additionally, the responses from FcgRIIb^−/− macrophages were more prominent than wild-type (WT) cells as determined by (i) supernatant cytokines (TNF-α, IL-6, and IL-10), (ii) expression of the inflammation associated genes (NF-κB, aryl hydrocarbon receptor, iNOS, IL-1β and activating-FcgRIV) and cell-surface CD-86 (a biomarker of M1 macrophage polarization), and (iii) cell apoptosis (Annexin V), with the lower inhibitory-FcgRIIb expression. Moreover, 8-week-administration of 1,4-CQ in 8 week old FcgRIIb^−/− mice, a genetic-prone lupus-like model, enhanced lupus characteristics as indicated by anti-dsDNA, serum creatinine, proteinuria, endotoxemia, gut-leakage (FITC-dextran), and glomerular immunoglobulin deposition. In conclusion, an Ahr activation worsened the disease severity in FcgRIIb^−/− mice possibly through the enhanced inflammatory responses. The deficiency of inhibitory-FcgRIIb in these mice, at least in part, prominently enhanced the pro-inflammatory responses. Our data suggest that patients with lupus might be more vulnerable to environmental pollutants. Full article

(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)

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