Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin

Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a β-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.Fil: Russo, Ashley J.. UConn Health School of Medicine; Estados UnidosFil: Vasudevan, Swathy O.. UConn Health School of Medicine; Estados UnidosFil: Mendez Huergo, Santiago Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kumari, Puja. UConn Health School of Medicine; Estados UnidosFil: Menoret, Antoine. UConn Health School of Medicine; Estados UnidosFil: Duduskar, Shivalee. Jena University Hospital; AlemaniaFil: Wang, Chengliang. UConn Health School of Medicine; Estados UnidosFil: Pérez Sáez, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fettis, Margaret M.. University of Florida; Estados UnidosFil: Li, Chuan. UConn Health School of Medicine; Estados UnidosFil: Liu, Renjie. University of Florida; Estados UnidosFil: Wanchoo, Arun. University of Florida; Estados UnidosFil: Chandiran, Karthik. UConn Health School of Medicine; Estados UnidosFil: Ruan, Jianbin. UConn Health School of Medicine; Estados UnidosFil: Vanaja, Sivapriya Kailasan. UConn Health School of Medicine; Estados UnidosFil: Bauer, Michael. Jena University Hospital; AlemaniaFil: Sponholz, Christoph. Jena University Hospital; AlemaniaFil: Hudalla, Gregory A.. University of Florida; Estados UnidosFil: Vella, Anthony T.. UConn Health School of Medicine; Estados UnidosFil: Zhou, Beiyan. UConn Health School of Medicine; Estados UnidosFil: Deshmukh, Sachin D.. Jena University Hospital; AlemaniaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rathinam, Vijay A.. UConn Health School of Medicine; Estados Unido

Honokiol Induces Calpain-Mediated Glucose-Regulated Protein-94 Cleavage and Apoptosis in Human Gastric Cancer Cells and Reduces Tumor Growth

Background. Honokiol, a small molecular weight natural product, has been shown to possess potent anti-neoplastic and anti-angiogenic properties. Its molecular mechanisms and the ability of anti-gastric cancer remain unknown. It has been shown that the anti-apoptotic function of the glucose-regulated proteins (GRPs) predicts that their induction in neoplastic cells can lead to cancer progression and drug resistance. We explored the effects of honokiol on the regulation of GRPs and apoptosis in human gastric cancer cells and tumor growth. Methodology and Principal Findings. Treatment of various human gastric cancer cells with honokiol led to the induction of GRP94 cleavage, but did not affect GRP78. Silencing of GRP94 by small interfering RNA (siRNA) could induce cell apoptosis. Treatment of cells with honokiol or chemotherapeutics agent etoposide enhanced the increase in apoptosis and GRP94 degradation. The calpain activity and calpain-II (m-calpain) protein (but not calpain-I (mu-calpain)) level could also be increased by honokiol. Honokiol-induced GRP94 down-regulation and apoptosis in gastric cancer cells could be reversed by siRNA targeting calpain-II and calpain inhibitors. Furthermore, the results of immunofluorescence staining and immunoprecipitation revealed a specific interaction of GRP94 with calpain-II in cells following honokiol treatment. We next observed that tumor GRP94 over-expression and tumor growth in BALB/c nude mice, which were inoculated with human gastric cancer cells MKN45, are markedly decreased by honokiol treatment. Conclusions and Significance. These results provide the first evidence that honokiol-induced calpain-II-mediated GRP94 cleavage causes human gastric cancer cell apoptosis. We further suggest that honokiol may be a possible therapeutic agent to improve clinical outcome of gastric cancer

µ-Calpain Conversion of Antiapoptotic Bfl-1 (BCL2A1) into a Prodeath Factor Reveals Two Distinct alpha-Helices Inducing Mitochondria-Mediated Apoptosis

Anti-apoptotic Bfl-1 and pro-apoptotic Bax, two members of the Bcl-2 family sharing a similar structural fold, are classically viewed as antagonist regulators of apoptosis. However, both proteins were reported to be death inducers following cleavage by the cysteine protease µ-calpain. Here we demonstrate that calpain-mediated cleavage of full-length Bfl-1 induces the release of C-terminal membrane active α-helices that are responsible for its conversion into a pro-apoptotic factor. A careful comparison of the different membrane-active regions present in the Bfl-1 truncated fragments with homologous domains of Bax show that helix α5, but not α6, of Bfl-1 induces cell death and cytochrome c release from purified mitochondria through a Bax/Bak-dependent mechanism. In contrast, both helices α5 and α6 of Bax permeabilize mitochondria regardless of the presence of Bax or Bak. Moreover, we provide evidence that the α9 helix of Bfl-1 promotes cytochrome c release and apoptosis through a unique membrane-destabilizing action whereas Bax-α9 does not display such activities. Hence, despite a common 3D-structure, C-terminal toxic domains present on Bfl-1 and Bax function in a dissimilar manner to permeabilize mitochondria and induce apoptosis. These findings provide insights for designing therapeutic approaches that could exploit the cleavage of endogenous Bcl-2 family proteins or the use of Bfl-1/Bax-derived peptides to promote tumor cell clearance

The Argentine deep sea: a new strategic frontier for sustainable development

The deep-sea ecosystems and biodiversity of Argentina are sensitive to the effects of climate variation such as warming, oxygen loss, and ocean acidification. This vulnerability is due to specific characteristics such as the presence of long-lived species, which can live for over 4,000 years, with very slow growth and reproduction rates, which depend on habitats with complex configurations. As a result, many deep-sea ecosystems affected by disturbances have a low probability of recovery, and if recovery occurs, it may take hundreds or even thousands of years. This document synthesizes the results of a Specialist Workshop that reviewed the current state of scientific knowledge and discussed its application to the management of Argentina’s deep sea, from an ecosystem-based perspective that considers climate variability. Argentina’s deep sea, spans depths ranging from 200 to 6,000 m, covering more than 70% of the national maritime territory, with an approximate area of 4.6 million km2. In the Argentine seabed, geomorphological and oceanographic complexity indicates a high potential to support extensive benthic biodiversity. However, knowledge about its ecosystems and the environmental management policies for this vast Argentine territory have been limited and fragmented, particularly regarding the incorporation of climate-related variables. Designing effective policies to protect its biodiversity and the multiple benefits these ecosystems provide to society implies robust technical advice, for which it is essential to strengthen scientific knowledge on Argentina’s deep-sea ecosystems and their interaction with climate variability, as well as sustained coordination and collaboration among all relevant sectors.Los ecosistemas del mar profundo argentino y su biodiversidad son sensibles a los efectos de la variación climática como el calentamiento, la pérdida de oxígeno y la acidificación oceánica. Esta vulnerabilidad se debe a características particulares como la presencia de especies longevas, con tasas de crecimiento y de reproducción muy lentas, que dependen de hábitats de configuraciones complejas. Como consecuencia, muchos ecosistemas del mar profundo afectados por perturbaciones tienen baja probabilidad de recuperarse, y si lo hicieran, requerirían cientos o miles de años. Este trabajo sintetiza los resultados de un Taller de Especialistas que permitió revisar el estado actual de conocimiento científico y de su aplicación a la gestión del mar profundo argentino, desde un enfoque ecosistémico que contemple la variación climática. El mar profundo de la Argentina abarca profundidades de entre 200 y 6.000 m, lo que representa más del 70% del territorio marítimo nacional, con una superficie aproximada de 4,6 millones de km2. En el fondo marino argentino, la complejidad geomorfológica y oceanográfica indica un alto potencial para sostener una enorme biodiversidad asociada al fondo. Sin embargo, el conocimiento sobre sus ecosistemas y las políticas de gestión ambiental de este vasto territorio argentino han sido limitados y fragmentados, especialmente en lo que respecta a la incorporación de la variable climática. Diseñar políticas efectivas que protejan su biodiversidad y los múltiples beneficios que aporta a la sociedad implica: i) un asesoramiento técnico robusto, para lo cual, es esencial fortalecer el conocimiento científico sobre los ecosistemas del mar profundo argentino y su interacción con la variación climática; y ii) una articulación y colaboración sostenida entre todos los sectores involucrados

Noncanonical Inflammasome-Induced release of Alarmins during Sepsis

Abstract Sepsis is a life-threatening disease caused by the immune system’s response to infection that results in excessive inflammation, organ damage and often death. In fact, sepsis is the leading cause of death in intensive care units and is responsible for more than 250,000 deaths every year in the USA. Activation of inflammatory caspases, such as caspase-11 by lipopolysaccharide (LPS) from Gram-negative bacteria, is a key mechanism of innate immune defense against infection. Intracellular sensing of LPS by caspase-11 results in pyroptosis, maturation of caspase-1, IL-1β and IL-18 and unconventional secretion of intracellular proteins that lack a leader sequence for conventional secretion via endoplasmic reticulum-Golgi route. These proteins can act as alarmins or damage associated molecular patterns (DAMPs) to regulate the inflammatory response and therefore play an important role during infectious diseases. However, caspase-11-dependent release of alarmins and DAMPs following noncanonical inflammasome activation is poorly characterized. Using a proteomics approach involving ProteomeLab’s PF2D fractionation system followed by mass spectrometry, we have profiled several new alarmins released in a caspase-11 dependent manner following Gram-negative bacterial infection. By employing various mutant mice and cells, we have defined the molecular and cellular mechanisms underlying the release of a candidate alarmin as a consequence of noncanonical inflammasome activation in vitro and in vivo. Importantly, our in vivo studies demonstrate a critical role for this alarmin in LPS shock. Overall, these findings provide new insights into potential biomarkers and therapeutic targets for blocking the lethal inflammation in sepsis.</jats:p

Une histoire du Proche-Orient au temps présent

Les recherches et l'enseignement de Nadine Picaudou (professeur d’histoire des sociétés arabes contemporaines à l’université Paris 1 Panthéon-Sorbonne jusqu’en 2010) offrent un aperçu saisissant des évolutions de l’histoire et du métier des historiens du Proche-Orient contemporain. Les études réunies dans ce volume et écrites à l’occasion de son départ de l’université par des chercheurs de disciplines variées retracent bien plus que le parcours intellectuel d’une historienne du Proche-Orient. Elles mettent en lumière l’apport croissant des sciences sociales, l’influence continue de terrains particuliers et des conflits de la région (Palestine, Liban), l’évolution des thèmes de recherche et celle des questionnements de la société sur l’histoire contemporaine et parfois très actuelle du Proche-Orient (Islam et modernité, place des femmes, formation et rôle de l’armée, printemps arabes). Avec ces études, c’est l’ensemble du Proche-Orient qui est abordé, de la Turquie à l’Arabie Saoudite et du xixe siècle à l’année 2014, dans un souci de dialogue constant entre l’histoire et les sciences sociales et humaines - dialogue qui a caractérisé le travail de Nadine Picaudou

A Cognitive Management Framework for Empowering the Internet of Things

This work presents a Cognitive Management framework for empowering the Internet of Things (IoT). This framework has the ability to dynamically adapt its behaviour, through self-management functionality, taking into account information and knowledge (obtained through machine learning) on the situation (e.g., internal status and status of environment), as well as policies (designating objectives, constraints, rules, etc.). Cognitive technologies constitute a unique and efficient approach for addressing the technological heterogeneity of the IoT and obtaining situation awareness, reliability and efficiency. The paper also presents a first indicative implementation of the proposed framework, comprising real sensors and actuators. The preliminary results of this work demonstrate high potential towards self-reconfigurable IoT