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Danger signal

R Halbgebauer, C Q Schmidt, C M Karsten, A Ignatius, M Huber-Lang
During local and systemic inflammation, the complement system and neutrophil granulocytes are activated not only by pathogens, but also by released endogenous danger signals. It is recognized increasingly that complement-mediated neutrophil activation plays an ambivalent role in sepsis pathophysiology. According to the current definition, the onset of organ dysfunction is a hallmark of sepsis. The preceding organ damage can be caused by excessive complement activation and neutrophil actions against the host, resulting in bystander injury of healthy tissue...
February 14, 2018: Seminars in Immunology
Tao Gong, Yanqing Yang, Tengchuan Jin, Wei Jiang, Rongbin Zhou
The assembly of the NLRP3 inflammasome can promote the release of IL-1β/IL-18 and initiate pyroptosis. Accordingly, the dysregulation of NLRP3 inflammasome activation is involved in a variety of human diseases, including gout, diabetes, and Alzheimer's disease. NLRP3 can sense a variety of structurally unrelated pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to trigger inflammation, but the unifying mechanism of NLRP3 activation is still poorly understood. Increasing evidence suggests that intracellular ions, such as K + , Ca 2+ , and Cl - , have a significant role in NLRP3 inflammasome activation...
February 13, 2018: Trends in Immunology
Najwa Issa, Nina Guillaumot, Emilie Lauret, Nicolas Matt, Christine Schaeffer-Reiss, Alain Van Dorsselaer, Jean-Marc Reichhart, Florian Veillard
Microbial or endogenous molecular patterns as well as pathogen functional features can activate innate immune systems. Whereas detection of infection by pattern recognition receptors has been investigated in details, sensing of virulence factors activities remains less characterized. In Drosophila, genetic evidences indicate that the serine protease Persephone belongs to a danger pathway activated by abnormal proteolytic activities to induce Toll signaling. However, neither the activation mechanism of this pathway nor its specificity has been determined...
February 15, 2018: Molecular Cell
Anindya Bhattacharya
The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and in vivo effects of brain-penetrant P2X7 antagonists. Likewise, significant progress has been made around the medicinal chemistry of CNS P2X7 ligands, as antagonists for in vivo target validation in models of CNS diseases, to identification of two clinical compounds (JNJ-54175446 and JNJ-55308942) and finally, discovery of P2X7 PET ligands...
2018: Frontiers in Pharmacology
Edward J Schenck, Kevin C Ma, Santosh B Murthy, Augustine M K Choi
OBJECTIVES: Sterile and infectious critical illnesses often result in vasoplegic shock and a robust systemic inflammatory response that are similar in presentation. The innate immune system is at the center of the response to both infectious and traumatic insults. Damage-associated molecular patterns are small molecules that are released from stressed or dying cells. Damage-associated molecular patterns activate pattern recognition receptors and coordinate the leading edge of the innate immune response...
February 13, 2018: Critical Care Medicine
Flavia Radogna, Marc Diederich
Cancer is evading the host's defense mechanisms leading to avoidance of immune destruction. During tumor progression, immune-evading cancer cells arise due to selective pressure from the hypoxic and nutrient-deprived microenvironment. Thus, therapies aiming at re-establishing immune destruction of pathological cells constitute innovating anti-cancer strategies. Accumulating evidence suggests that selected conventional chemotherapeutic drugs increase the immunogenicity of stressed and dying cancer cells by triggering a form of cell death called immunogenic cell death (ICD), which is characterized by the release of danger-associated molecular patterns (DAMPs)...
February 10, 2018: Biochemical Pharmacology
Erivan S Ramos-Junior, Ana Carolina Morandini
Pyroptosis is a lytic type of programmed cell death that was traditionally associated with the involvement of inflammatory caspases, such as caspase-1. These inflammatory caspases are activated within multi-protein complexes called inflammasomes that are assembled in response to invading pathogens and/or danger signals. Pyroptotic cell death was suggested to evolve via the formation of pores in the plasma membrane, but the exact mechanism underlying the formation of these pores remained unclear. Recently, gasdermin D, a member of the gasdermin protein family was identified as a caspase substrate and essential effector of pyroptosis, being identified as the protagonist of membrane pore formation...
December 2017: Biomedical Journal
Hanna Bonnekoh, Jörg Scheffel, Naotomo Kambe, Karoline Krause
The concept of autoinflammation was proposed to define a new class of immune disorders categorized by self-directed inflammation that is driven via activation of innate immune pathways. Within innate immunity, inflammasomes serve as intracellular signaling platforms to endogenous danger molecules and pathogens. Their key function is the cleavage of pro-interleukin-1β (pro-IL-1β) into its active form to promote inflammation and programmed cell death. A growing number of inflammasome sensors were described, among which NLR family pyrin domain containing 3 (NLRP3) is the best-studied sensor...
March 2018: Immunological Reviews
Ho Liam Pock, Teo Yi Wei Bryan, Tan Puay Hoon, Jabed Iqbal, Linn Yeh Ching, Goh Yeow Tee, Tan Kar Wai, Toh Han Chong, Ong Kong Wee, Yeoh Kheng Wei
AIM: The new radioimmunotherapeutic regime GAP15R aims to stimulate glucocorticoid-induced TNF-related protein (G) to overcome Treg suppression; add IFN-α (A) to promote inflammatory milieu; block PD1 (P) to disinhibit T effector cytotoxicity; add IL-15 (15) to enhance danger signals & T-cell expansion; and apply radiation (R) at critical time point to sustain localized inflammation. Patients & methods/materials & methods: This was tested in a murine 4T1 metastatic breast carcinoma model given GAP15R with regular monitoring of tumor volume and complications...
February 1, 2018: Immunotherapy
Kazuhide Inoue, Makoto Tsuda
Acute nociceptive pain is a key defence system that enables the detection of danger signals that threaten homeostasis and survival. However, chronic pain (such as the neuropathic pain that occurs after peripheral nerve injury) is not simply a consequence of the continuity of acute nociceptive signals but rather of maladaptive nervous system function. Over recent decades, studies have provided evidence for the necessity and sufficiency of microglia for the alterations in synaptic remodelling, connectivity and network function that underlie chronic pain and have shed light on the underlying molecular and cellular mechanisms...
February 8, 2018: Nature Reviews. Neuroscience
Abigail Zieman, Pierre A Coulombe
The type I intermediate filament keratin 16 (K16) is constitutively expressed in ectoderm-derived appendages and is inducibly expressed in the epidermis upon barrier-compromising challenges. Dominantly-acting missense alleles in KRT16 are causative for pachyonychia congenita (PC), a genodermatosis involving debilitating palmoplantar keratoderma (PPK), nail dystrophy, oral lesions and, frequently, alterations in glands and hair. C57Bl/6;Krt16-/- mice develop oral lesions early after birth and PC-like PPK lesions as young adults...
February 6, 2018: Experimental Dermatology
Daiane Boff, Helena Crijns, Mauro M Teixeira, Flavio A Amaral, Paul Proost
Septic arthritis is an inflammatory joint disease that is induced by pathogens such as Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by inflammatory mediators including microbial danger signals and cytokines and is accompanied by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of chemoattractants including formylated peptides from the infectious agent or dying cells, host-derived leukotrienes, complement proteins and chemokines...
February 5, 2018: International Journal of Molecular Sciences
Tiphaine Delaunay, Mathilde Violland, Nicolas Boisgerault, Soizic Dutoit, Virginie Vignard, Christian Münz, Monique Gannage, Brigitte Dréno, Kristine Vaivode, Dace Pjanova, Nathalie Labarrière, Yaohe Wang, E Antonio Chiocca, Fabrice Le Boeuf, John C Bell, Philippe Erbs, Frédéric Tangy, Marc Grégoire, Jean-François Fonteneau
Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumor-associated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1...
2018: Oncoimmunology
Yvonne Mödinger, Bettina Löffler, Markus Huber-Lang, Anita Ignatius
An integral part of innate immunity is the complement system, a defence system, consisting of fluid-phase and cell surface-bound proteins. Its role to ensure adequate responses to danger factors and thus promoting host defence against pathogens has been well described already for decades. Recently, numerous further reaching functions of complement have been discovered, among these are tissue homeostasis and regeneration, also with respect to the skeletal system. The influence of complement activation on bone was recognised first in pathological conditions of inflamed bone tissue and surrounding areas, observed, for example, in rheumatoid arthritis and osteoarthritis...
January 29, 2018: Seminars in Immunology
Afrouzeh Hashemi-Monfared, Masoumeh Firouzi, Zahra Bahrami, Hamid Zahednasab, Mohammad Hossein Harirchian
Microglia are the resident macrophages patrolling the central nervous system (CNS) to find dangerous signals and infectious agents mediating catastrophic cascades resulting in neuronal degeneration. Their morphological and biochemical properties made them enable to swift activation in response to neural insults and site-directed phagocytosis. Beside of beneficial roles in homeostasis of the brain and spinal cord, microglia can be participating in neuronal destruction and propagation of inflammation when they are unregulated or hyper-activated...
January 27, 2018: Journal of Neuroimmunology
Anna M Marzeda, Kim S Midwood
To protect against danger, the innate immune system must promptly and accurately sense alarm signals, and mount an appropriate response to restore homeostasis. One endogenous trigger of immunity is tenascin-C, a large hexameric protein of the extracellular matrix. Upregulated upon tissue injury and cellular stress, tenascin-C is expressed during inflammation and tissue remodeling, where it influences cellular behavior by interacting with a multitude of molecular targets, including other matrix components, cell surface proteins, and growth factors...
January 1, 2018: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Eisuke Dohi, Eric Y Choi, Indigo V L Rose, Akiho S Murata, Sharon Chow, Minae Niwa, Shin-Ichi Kano
Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is expressed in nuclei and secreted as alarmin upon cellular damage to deliver a danger signal to the surrounding cells. Previous studies showed that IL-33 is expressed in the brain and that it is involved in neuroinflammatory and neurodegenerative processes in both humans and rodents. Nevertheless, the role of IL-33 in physiological brain function and behavior remains unclear. Here, we have investigated the behaviors of mice lacking IL-33 (Il33-/- mice)...
November 2017: ENeuro
Mariane T de Paula, Márcia R P Silva, Stífani M Araújo, Vandreza C Bortolotto, Illana K Martins, Giulianna E Macedo, Jeferson L Franco, Thaís Posser, Marina Prigol
Maternal obesity and metabolic diseases are two of the most important potential dangers to offspring, given that impaired offspring may cause deficiencies that impair the adult life and health. This study evaluated the oxidative damage, the enzymatic antioxidant defenses, and the enzymes of fatty acid metabolism, such as Acyl-CoA Synthetase and Acetyl-CoA Synthetase (mRNA expression levels), as well as the modulation of cell stress signaling pathway, as Hsp83, and gene expression and insulin-like peptide DILP6 in Drosophila melanogaster models that received a high fat diet (HFD) (10% and 20% of coconut oil) throughout their development period...
January 29, 2018: Journal of Cellular Biochemistry
V B Krylov, D A Argunov, A S Solovev, M I Petruk, A G Gerbst, A S Dmitrenok, A S Shashkov, J-P Latgé, N E Nifantiev
The synthesis of model oligosaccharides related to antigenic galactomannans of the dangerous fungal pathogen Aspergillus fumigatus has been performed employing pyranoside-into-furanoside (PIF) rearrangement and controlled O(5) → O(6) benzoyl migration as key synthetic methods. The prepared compounds along with some previously synthesized oligosaccharides were studied by NMR spectroscopy with the full assignment of 1H and 13C signals and the determination of 13C NMR glycosylation effects. The obtained NMR database on 13C NMR chemical shifts for oligosaccharides representing galactomannan fragments forms the basis for further structural analysis of galactomannan related polysaccharides by a non-destructive approach based on the calculation of the 13C NMR spectra of polysaccharides by additive schemes...
January 29, 2018: Organic & Biomolecular Chemistry
Caroline Maria Oliveira Volpe, Pedro Henrique Villar-Delfino, Paula Martins Ferreira Dos Anjos, José Augusto Nogueira-Machado
Chronic or intermittent hyperglycemia is associated with the development of diabetic complications. Several signaling pathways can be altered by having hyperglycemia in different tissues, producing oxidative stress, the formation of advanced glycation end products (AGEs), as well as the secretion of the pro-inflammatory cytokines and cellular death (pathological autophagy and/or apoptosis). However, the signaling pathways that are directly triggered by hyperglycemia appear to have a pivotal role in diabetic complications due to the production of reactive oxygen species (ROS), oxidative stress, and cellular death...
January 25, 2018: Cell Death & Disease
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