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Ashley A Basiorka, Kathy L McGraw, Erika A Eksioglu, Xianghong Chen, Joseph Johnson, Ling Zhang, Qing Zhang, Brittany A Irvine, Thomas Cluzeau, David A Sallman, Eric Padron, Rami Komrokji, Lubomir Sokol, Rebecca C Coll, Avril A B Robertson, Matthew A Cooper, John L Cleveland, Luke A O'Neill, Sheng Wei, Alan F List
Despite genetic heterogeneity, myelodysplastic syndromes (MDS) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDS is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem/progenitor cells (HSPC) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of IL-1β and IL-18 and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPC and bone marrow plasma...
October 13, 2016: Blood
Meriam Nefla, Dirk Holzinger, Francis Berenbaum, Claire Jacques
Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy)...
October 13, 2016: Nature Reviews. Rheumatology
Nerissa Lakhan, Natalie E Stevens, Kerrilyn R Diener, John D Hayball
Adjuvants are used to enhance the immune response against specific antigens for the production of antibodies, with the choice of adjuvant most critical for poorly immunogenic and self-antigens. This study quantitatively and qualitatively evaluated CoVaccine HT™ and Freund's adjuvants for eliciting therapeutic ovine polyclonal antibodies targeting the endogenous alarmin, high mobility group box-1 (HMGB1). Sheep were immunised with HMGB1 protein in CoVaccine HT™ or Freund's adjuvants, with injection site reactions and antibody titres periodically assessed...
September 30, 2016: Journal of Immunological Methods
Ralf Willebrand, David Voehringer
Eosinophils are major effector cells during allergic responses and helminth infections. Recent studies further highlight eosinophils as important players in many other biological processes. Therefore it is important to understand how these cells can be modulated in terms of survival and effector function. In the present study we investigated how eosinophils respond to the alarmin IL-33. We show that IL-33 promotes eosinophil survival in a ST2- and MyD88-dependent manner. IL-33-mediated protection from apoptosis was dependent on autocrine GM-CSF release...
2016: PloS One
Jan Máca, Filip Burša, Pavel Ševčík, Peter Sklienka, Michal Burda, Michal Holub
PURPOSE: Tissue injury causing immune response is an integral part of surgical procedure. Evaluation of the degree of surgical trauma could help to improve postoperative management and determine the clinical outcomes. MATERIALS AND METHODS: We analyzed serum levels of alarmins, including S100A5, S100A6, S100A8, S100A9, S100A11, and S100A12; high-mobility group box 1; and heat-shock protein 70, after elective major abdominal surgery (n = 82). Blood samples were collected for three consecutive days after surgery...
September 30, 2016: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
Xiao-Yuan Qiu, Lu Sun, Xue-Ling Han, Ying Chang, Lan Cheng, Li-Rong Yin
Chorioamnionitis is associated with an increased risk of spontaneous preterm birth. The aim of this study was to investigate the serum levels of high mobility group box-1 (HMGB1) in pregnancies with histological chorioamnionitis (HCA)-associated preterm labor (PTL) with intact membranes or preterm premature rupture of membranes (PPROM), and to access the role of serum HMGB1 in HCA and HCA-associated PTL. A total of 190 pregnant women were enrolled in this study: PLT patients with (n = 28) or without HCA (n = 36), PPROM patients with (n = 26) or without HCA (n = 65), and non-HCA PTL controls (n = 35)...
August 12, 2016: Gynecological Endocrinology
Mathieu Nadeau-Vallee, Dima Obari, Julia Palacios, Marie-Eve Brien, Cyntia Duval, Sylvain Chemtob, Sylvie Girard
Inflammation is central to successful reproduction. In the last decade, important advances have been made in regards to endogenous, and therefore non-infectious, initiators of inflammation which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs) and their involvement in reproduction has only recently begun to be unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating impact on pregnancy outcomes...
September 27, 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Ralf Willebrand, David Voehringer
PURPOSE OF REVIEW: Eosinophils are a subset of granulocytes generally associated with type 2 immune responses. They can contribute to protection against helminths but also mediate pro-inflammatory functions during allergic immune responses. Only recently, eosinophils were also found to exert many other functions such as regulation of glucose and fat metabolism, thermogenesis, survival of plasma cells, and antitumor activity. The mechanisms that control eosinophil development and survival are only partially understood...
September 26, 2016: Current Opinion in Hematology
Ayako Matsuki, Hiroaki Takatori, Sohei Makita, Masaya Yokota, Tomohiro Tamachi, Akira Suto, Kotaro Suzuki, Koichi Hirose, Hiroshi Nakajima
BACKGROUND: Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and ILC1s; however, the roles of T-bet in lung ILC2s remain unknown. OBJECTIVE: To determine the role of T-bet in ILC2-mediated airway inflammation. METHODS: The expression of T-bet in lung ILCs (defined as Thy1...
September 23, 2016: Journal of Allergy and Clinical Immunology
Miha Lavric, María Auxiliadora Miranda-García, Dirk Holzinger, Dirk Foell, Helmut Wittkowski
Alarmins are endogenous molecules with homeostatic roles that have reached the focus of research in inflammatory arthritis in the last two decades, mostly due to their ability to indicate tissue related damage after active or passive release from injured cells. From HMGB1, S100A8/A9 and S100A12 proteins, over heat-shock proteins (HSPs) and purine metabolites (e.g. uric acid, ATP) to altered matrix proteins and interleukin-33 (IL-33), a number of alarmins have been determined until now as having a role in rheumatoid arthritis, psoriatic and juvenile idiopathic arthritis, as well as spondyloarthritis and gout...
September 19, 2016: Joint, Bone, Spine: Revue du Rhumatisme
J G Yeo, J Leong, T Arkachaisri, Y Cai, B H D Teo, J H T Tan, L Das, J Lu
Effective clearance of apoptotic cells by phagocytes prevents the release of intracellular alarmins and manifestation of autoimmunity. This prompt efferocytosis is complemented by intracellular proteolytic degradation that occurs within the apoptotic cells and in the efferosome of the phagocytes. Although the role of extracellular proteases in apoptotic cells clearance is unknown, the strong association of congenital C1s deficiency with Systemic Lupus Erythematosus highlights the protective nature that this extracellular protease has against autoimmunity...
2016: Cell Death Discovery
Forrest Jessop, Raymond F Hamilton, Joseph F Rhoderick, Pamela K Shaw, Andrij Holian
Autophagy is an important metabolic mechanism that can promote cellular survival following injury. The specific contribution of autophagy to silica-induced inflammation and disease is not known. The objective of these studies was to determine the effects of silica exposure on the autophagic pathway in macrophages, as well as the general contribution of autophagy in macrophages to inflammation and disease. Silica exposure enhanced autophagic activity in vitro in Bone Marrow derived Macrophages and in vivo in Alveolar Macrophages isolated from silica-exposed mice...
October 15, 2016: Toxicology and Applied Pharmacology
Shuo Zheng, Apparao B Kummarapurugu, Daniel K Afosah, Nehru Viji Sankaranarayanan, Rio S Boothello, Umesh R Desai, Thomas Kennedy, Judith A Voynow
High mobility group box 1 (HMGB1) is an alarmin released from macrophages following infection or inflammation, and a biomarker of lung disease progression in cystic fibrosis. We reported that 2-O, 3-O desulfated heparin (ODSH) inhibits release of HMGB1 from murine macrophages triggered by neutrophil elastase (NE) both in vivo and in vitro. HMGB1 shuttles between the nucleus and the cytoplasm. When acetylated at lysine residues in the nuclear localization signal domains, HMGB1 is sequestered in the cytoplasm and is fated for secretion...
September 1, 2016: American Journal of Respiratory Cell and Molecular Biology
Damien Bertheloot, Eicke Latz
Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline-encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells...
August 29, 2016: Cellular & Molecular Immunology
Peter K Smith, Madhan Masilamani, Xiu-Min Li, Hugh A Sampson
The incidence of food allergy has increased dramatically in the last few decades in westernized developed countries. We propose that the Western lifestyle and diet promote innate danger signals and immune responses through production of "alarmins." Alarmins are endogenous molecules secreted from cells undergoing nonprogrammed cell death that signal tissue and cell damage. High molecular group S (HMGB1) is a major alarmin that binds to the receptor for advanced glycation end-products (RAGE). Advanced glycation end-products (AGEs) are also present in foods...
July 15, 2016: Journal of Allergy and Clinical Immunology
Jing Chang, Yue-Feng Xia, Ma-Zhong Zhang, Li-Ming Zhang
Interleukin (IL)-33, a member of the IL-1 cytokine super-family, acts as both a traditional cytokine and an intracellular nuclear factor. It is generally released from damaged immune cells and signals through its receptor ST2 in an autocrine and paracrine fashion, plays important roles in type-2 innate immunity, and functions as an "alarmin" or a danger signal for cellular damage or cellular stress. Here, we review recent advances of the role of IL-33 in lung injury and explore its potential significance as an attractive therapeutic target...
2016: Translational Perioperative and Pain Medicine
Laura E Felley, Akshat Sharma, Erin Theisen, James C Romero-Masters, John-Demian Sauer, Jenny E Gumperz
The cytokine IL-1β plays a central role in inflammatory responses that are initiated by microbial challenges, as well as in those that are due to endogenous processes (often called sterile inflammation). IL-1β secretion that occurs independently of microbial stimulation is typically associated with the presence of endogenous alarmins, such as extracellular ATP (an indicator of cytopathic damage). In this study, we show that IL-2-activated human invariant NKT (iNKT) cells stimulate the secretion of IL-1β protein by human peripheral blood monocytes in a manner that requires neither the presence of microbial compounds nor signaling through the extracellular ATP receptor P2X7 Monocyte IL-1β production was specifically induced by iNKT cells, because similarly activated polyclonal autologous T cells did not have this effect...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Tina Rubić-Schneider, Nicole Carballido-Perrig, Camille Regairaz, Layla Raad, Sandra Jost, Celine Rauld, Brigitte Christen, Grazyna Wieczorek, Robert Kreutzer, Janet Dawson, Günther Lametschwandner, Amanda Littlewood-Evans, José M Carballido
BACKGROUND: Succinate, in addition to its role as an intermediary of the citric acid cycle, acts as an alarmin, initiating and propagating danger signals resulting from tissue injury or inflammatory stimuli. The contribution of this immune sensing pathway to the development of allergic and inflammatory responses is unknown. METHODS: Ear thickness of wild type (wt) and Sucnr1 deficient (Sucnr1 (-/-) ) mice, sensitized and challenged with oxazolone, was used as a criterion to assess the relevance of SUCNR1/GPR91 expression mediating allergic contact dermatitis (ACD)...
August 16, 2016: Allergy
Neal L Millar, Charlotte O'Donnell, Iain B McInnes, Elizabeth Brint
IL-33 is a member of the IL-1 family of cytokines. IL-33 is predominantly located within the nucleus of cells where it plays a role in gene regulation. Given the right combination of signals and cellular damage, stored IL-33 is released from the cell where it can interact with its receptor ST2, triggering danger-associated responses and act as a cellular "alarmin". Whilst IL-33/ST2 signalling has been shown to induce potent pro-inflammatory responses that can be detrimental in certain disease states, a dichotomous, protective role of IL-33 in promoting wound healing has also emerged in multiple tissues types...
August 10, 2016: Seminars in Cell & Developmental Biology
Hans-Joachim Anders
Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1β and of the alarmin IL-1α Dying cells release IL-1α also, independently of the inflammasome. Both IL-1α and IL-1β ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release...
September 2016: Journal of the American Society of Nephrology: JASN
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