scholarly journals Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery

2020 ◽  
Vol 295 (51) ◽  
pp. 17842-17851
Author(s):  
Robert S. Munford ◽  
Jerrold P. Weiss ◽  
Mingfang Lu
Keyword(s):  
Recent Progress ◽  
Tissue Injury ◽  
Host Defenses ◽  
Host Animal ◽  
Gram Negative ◽  
Microbial Structures ◽  
Bacterial Lipopolysaccharides ◽  
Molecular Patterns ◽  
Acyloxyacyl Hydrolase ◽  
Pulmonary Allergens

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.

scholarly journals Mitophagy: mechanisms, pathophysiological roles, and analysis

2012 ◽  
Vol 393 (7) ◽  
pp. 547-564 ◽  
Author(s):  
Wen-Xing Ding ◽  
Xiao-Ming Yin
Keyword(s):  
Cell Death ◽  
Blood Cells ◽  
Energy Homeostasis ◽  
Recent Progress ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Terminal Differentiation ◽  
Cellular Functions ◽  
Drug Induced ◽  
Cellular Energy

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.

scholarly journals Type I interferon responses to ischemic injury begin in the bone marrow of mice and humans and depend on Tet2, Nrf2, and Irf3

2019 ◽  
Author(s):  
David M. Calcagno ◽  
Richard P. Ng ◽  
Avinash Toomu ◽  
Claire Zhang ◽  
Kenneth Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Type I ◽  
Blood Neutrophils ◽  
Clinical Biomarker ◽  
Acute Mi ◽  
Molecular Patterns ◽  
Interferon Responses ◽  
Myeloid Progenitors

AbstractSterile tissue injury locally activates innate immune responses via interactions with damage associated molecular patterns (DAMPs). Here, by analyzing ∼120K single cell transcriptomes after myocardial infarction (MI) in mice and humans, we show neutrophil and monocyte subsets induce type I interferon (IFN) stimulated genes (ISGs) in myeloid progenitors of the bone marrow, far from the site of injury. In patients with acute MI, peripheral blood neutrophils and monocytes express ISGs at levels far beyond healthy individuals and comparable to patients with lupus. In the bone marrow of Tet2-/- mice, ISGs are spontaneously induced in myeloid progenitors and their progeny. In the heart, IFN responses are negatively regulated by Ccr2- resident macrophages in a Nrf2-dependent fashion. Our results show post-MI IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying post-MI IFN signaling in patients.

scholarly journals The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Monica Molteni ◽  
Sabrina Gemma ◽  
Carlo Rossetti
Keyword(s):  
Tissue Injury ◽  
Sterile Inflammation ◽  
Research Progress ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
The Family ◽  
Tlr4 Activation ◽  
Molecular Patterns

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

scholarly journals INCREASED RESISTANCE TO INFECTION AND ACCOMPANYING ALTERATION IN PROPERDIN LEVELS FOLLOWING ADMINISTRATION OF BACTERIAL LIPOPOLYSACCHARIDES

1956 ◽  
Vol 104 (3) ◽  
pp. 383-409 ◽  
Author(s):  
Maurice Landy ◽  
Louis Pillemer
Keyword(s):  
Defense Mechanisms ◽  
Bacterial Species ◽  
Complex Nature ◽  
Gram Negative ◽  
Resistance To Infection ◽  
Bacterial Lipopolysaccharides ◽  
Gram Negative Organisms ◽  
Incomplete Picture ◽  
Time Of Administration

It has been shown that injection of lipopolysaccharides, derived from a variety of Gram-negative bacterial species, evokes in mice a rapidly developing rise in resistance to infection with Gram-negative pathogens. This is accompanied by an elevation in properdin titer, at times to levels 2 to 3 times the normal. The rate, magnitude, and duration of these responses are dependent on many factors, the most important of which are the quantity and timing of the lipopolysaccharide administered. The increased resistance to infection evoked in mice by lipopolysaccharides was effective against infections produced by endotoxin-bearing organisms-bacterial species highly susceptible in vitro to the bactericidal action of the properdin system. Properdin titers of mice prior to infection provide an incomplete picture of the subsequent reaction of the host to the infective agent. Following infection with Gram-negative organisms, properdin levels accurately reflect the bacteriologic course and outcome of the infection. Thus, in control animals, properdin titers progressively declined and the animals died, while in mice appropriately treated with lipopolysaccharide, properdin levels were either maintained in the normal range or increased, depending on the dose and time of administration of lipopolysaccharide; this was always accompanied by successful management of the infection. The complex nature of the alterations produced in the host by lipopolysaccharides is stressed. It is pointed out that the increase in the ability of the host to cope with Gram-negative infections may be the result of stimulation of other defense mechanisms, in addition to the properdin system.

scholarly journals Acetaminophen-Induced Rat Hepatotoxicity Based on M1/M2-Macrophage Polarization, in Possible Relation to Damage-Associated Molecular Patterns and Autophagy

2020 ◽  
Vol 21 (23) ◽  
pp. 8998
Author(s):  
Yuka Tsuji ◽  
Mizuki Kuramochi ◽  
Hossain M. Golbar ◽  
Takeshi Izawa ◽  
Mitsuru Kuwamura ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Rat Model ◽  
Tissue Injury ◽  
Macrophage Polarization ◽  
Coagulation Necrosis ◽  
M2 Macrophage ◽  
Old Rats ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
M1 Type

Overdose of acetaminophen (APAP), an antipyretic drug, is an important cause of liver injury. However, the mechanism in the rat model remains undetermined. We analyzed APAP-induced hepatotoxicity using rats based on M1/M2-macrophage functions in relation to damage-associated molecular patterns (DAMPs) and autophagy. Liver samples from six-week-old rats injected with APAP (1000 mg/kg BW, ip, once) after 15 h fasting were collected at hour 10, and on days 1, 2, 3, and 5. Liver lesions consisting of coagulation necrosis and inflammation were seen in the affected centrilobular area on days 1 and 2, and then, recovered with reparative fibrosis by day 5. Liver exudative enzymes increased transiently on day 1. CD68+ M1-macrophages increased significantly on days 1 and 2 with increased mRNAs of M1-related cytokines such as IFN-g and TNF-α, whereas CD163+ M2-macrophages appeared later on days 2 and 3. Macrophages reacting to MHC class II and Iba1 showed M1-type polarization, and CD204+ macrophages tended to be polarized toward M2-type. At hour 10, interestingly, HMGB1 (representative DAMPs) and its related signals, TLR-9 and MyD88, as well as LC3B+ autophagosomes began to increase. Collectively, the pathogenesis of rat APAP hepatotoxicity, which is the first, detailed report for a rat model, might be influenced by macrophage functions of M1 type for tissue injury/inflammation and M2-type for anti-inflammatory/fibrosis; particularly, M1-type may function in relation to DAMPs and autophagy. Understanding the interplayed mechanisms would provide new insight into hepato-pathogenesis and contribute to the possible development of therapeutic strategies.

Molecular Simulations of Gram-Negative Bacterial Membranes Come of Age

2020 ◽  
Vol 71 (1) ◽  
pp. 171-188
Author(s):  
Wonpil Im ◽  
Syma Khalid
Keyword(s):  
Recent Progress ◽  
Cell Envelope ◽  
Molecular Simulations ◽  
Molecular Architecture ◽  
Future Directions ◽  
Gram Negative ◽  
Bacterial Membranes ◽  
Antibiotic Development ◽  
Multiple Cell ◽  
Made In

Gram-negative bacteria are protected by a multicompartmental molecular architecture known as the cell envelope that contains two membranes and a thin cell wall. As the cell envelope controls influx and efflux of molecular species, in recent years both experimental and computational studies of such architectures have seen a resurgence due to the implications for antibiotic development. In this article we review recent progress in molecular simulations of bacterial membranes. We show that enormous progress has been made in terms of the lipidic and protein compositions of bacterial systems. The simulations have moved away from the traditional setup of one protein surrounded by a large patch of the same lipid type toward a more bio-logically representative viewpoint. Simulations with multiple cell envelope components are also emerging. We review some of the key method developments that have facilitated recent progress, discuss some current limitations, and offer a perspective on future directions.

scholarly journals NOD-like receptors: major players (and targets) in the interface between innate immunity and cancer

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Fernando J. Velloso ◽  
Marina Trombetta-Lima ◽  
Valesca Anschau ◽  
Mari C. Sogayar ◽  
Ricardo G. Correa
Keyword(s):  
Innate Immunity ◽  
Tissue Injury ◽  
Large Family ◽  
Nuclear Factor Κb ◽  
Podospora Anserina ◽  
Host Responses ◽  
Interferon Response ◽  
Transcription Activator ◽  
Response Factors ◽  
Molecular Patterns

AbstractInnate immunity comprises several inflammation-related modulatory pathways which receive signals from an array of membrane-bound and cytoplasmic pattern recognition receptors (PRRs). The NLRs (NACHT (NAIP (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein) and Leucine-Rich Repeat (LRR) domain containing proteins) relate to a large family of cytosolic innate receptors, involved in detection of intracellular pathogens and endogenous byproducts of tissue injury. These receptors may recognize pathogen-associated molecular patterns (PAMPs) and/or danger-associated molecular patterns (DAMPs), activating host responses against pathogen infection and cellular stress. NLR-driven downstream signals trigger a number of signaling circuitries, which may either initiate the formation of inflammasomes and/or activate nuclear factor κB (NF-κB), stress kinases, interferon response factors (IRFs), inflammatory caspases and autophagy. Disruption of those signals may lead to a number of pro-inflammatory conditions, eventually promoting the onset of human malignancies. In this review, we describe the structures and functions of the most well-defined NLR proteins and highlight their association and biological impact on a diverse number of cancers.

scholarly journals Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury

2015 ◽  
Vol 308 (9) ◽  
pp. L855-L860 ◽  
Author(s):  
Robert Maile ◽  
Samuel Jones ◽  
Yinghao Pan ◽  
Haibo Zhou ◽  
Ilona Jaspers ◽  
...  
Keyword(s):  
North Carolina ◽  
Bacterial Infection ◽  
Injury Severity ◽  
Burn Injury ◽  
Tissue Injury ◽  
Cell Damage ◽  
Inhalation Injury ◽  
High Mobility Group Protein ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Bacterial infection is a major cause of morbidity affecting outcome following burn and inhalation injury. While experimental burn and inhalation injury animal models have suggested that mediators of cell damage and inflammation increase the risk of infection, few studies have been done on humans. This is a prospective, observational study of patients admitted to the North Carolina Jaycee Burn Center at the University of North Carolina who were intubated and on mechanical ventilation for treatment of burn and inhalational injury. Subjects were enrolled over a 2-yr period and followed till discharge or death. Serial bronchial washings from clinically indicated bronchoscopies were collected and analyzed for markers of tissue injury and inflammation. These include damage-associated molecular patterns (DAMPs) such as hyaluronic acid (HA), double-stranded DNA (dsDNA), heat-shock protein 70 (HSP-70), and high-mobility group protein B-1 (HMGB-1). The study population was comprised of 72 patients who had bacterial cultures obtained for clinical indications. Elevated HA, dsDNA, and IL-10 levels in bronchial washings obtained early (the first 72 h after injury) were significantly associated with positive bacterial respiratory cultures obtained during the first 14 days postinjury. Independent of initial inhalation injury severity and extent of surface burn, elevated levels of HA dsDNA and IL-10 in the central airways obtained early after injury are associated with subsequent positive bacterial respiratory cultures in patients intubated after acute burn/inhalation injury.

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