MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Objective: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. Design: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. Results: We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. Conclusions: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury

Perfluorinated Chemicals in Meromictic Lakes on the Northern Coast of Ellesmere Island, High Arctic Canada + Online Appendix 1 (See Article Tools)

Perfluorinated chemicals (PFCs) have been recorded in many types of marine and freshwater ecosystems. The aim of the present study was to examine meromictic lakes and their catchments on the far northern coast of Ellesmere Island, Nunavut, Canada, and to evaluate the results in the context of climate change. Our analyses revealed the presence of several PFCs in catchment snowpack, inflowing streams, lake water, and the aquatic food web of Lake A (83˚00ʹ N, 75˚30ʹ W), showing that dispersal of these contaminants reaches the northern limit of the terrestrial High Arctic. However, the concentrations were low (total PFCs: 27 – 754 pg L-1 for water, 134 – 848 pg L-1 for melted snow, 5 – 2149 pg g-1 wet weight for fish; PFOS: 66 pg g-1 dry weight in surficial sediments) and at or below values reported to date in the literature for other remote lakes. PFHpA, PFOA, and PFNA were the main compounds detected in water and melted snow, while PFNA, PFDA, and PFUnA were the predominant compounds in the aquatic biota, indicating their bioaccumulative potential. Salinity-temperature-depth profiles suggested that most of the present contaminant load enters the lake via streams and flows directly under the lake ice to the ocean. The onset of summer open water in this perennially ice-covered lake in response to climate warming, and the increased duration of open water in recent years, have implications for the distribution, transport, and retention of PFCs in Arctic lakes.Les composés perfluorés ont été retrouvés dans plusieurs types d’écosystèmes marins et d’eau douce. L’objectif de cette étude était d’étendre ces mesures à des lacs méromictiques situés sur la côte nord de l’île d’Ellesmere au Nunavut, et d’évaluer les résultats dans le contexte des changements climatiques. Nos analyses ont révélé la présence de plusieurs composés perfluorés dans la neige du bassin versant, les affluents, l’effluent, l’eau de lac, et le réseau alimentaire d’un de ces lacs, le lac A (83˚00ʹ N, 75˚30ʹ O). Ces résultats soulignent que la distribution de ces contaminants atteint la limite nordique de l’Arctique terrestre. Cependant, les concentrations mesurées étaient très faibles (au total : 27 – 754 pg L-1 pour l’eau, 134 – 848 pg L-1 pour la neige fondue, 5 – 2149 pg g-1 pour les poissons et PFOS : 66 pg g-1 dans les sédiments de surface) et en-dessous des valeurs publiées pour d’autres lacs de régions éloignées. PFHpA, PFOA et PFNA étaient les principaux composés détectés dans l’eau et la neige fondue alors que PFNA, PFDA et PFUnA étaient les composés prédominants pour le biote aquatique, indiquant leur potentiel de bioaccumulation. Des profils de salinité et de température ont suggéré que la majorité des conta- minants entre dans le lac via les affluents et s’écoule directement sous le couvert de glace jusqu’à l’océan. Les conditions d’eau libre observées pendant l’été dans ce lac auparavant couvert de glace en permanence, et la durée accrue des conditions d’eau libre des dernières années ont des implications pour la distribution, le transport et la rétention des composés perfluorés dans les lacs arctiques

Acceleration of gelation and promotion of mineralization of chitosan hydrogels by alkaline phosphatase

Item does not contain fulltextThermosensitive chitosan hydrogels containing sodium beta-glycerophosphate (beta-GP), whose gelation is induced by increasing temperature to body temperature, were functionalized by incorporation of alkaline phosphatase (ALP), an enzyme involved in mineralization of bone. ALP incorporation led to acceleration of gelation upon increase of temperature for four different chitosan preparations of differing molecular weight, as demonstrated by rheometric time sweeps at 37 degrees C. Hydrogels containing ALP were subsequently incubated in calcium glycerophosphate (Ca-GP) solution to induce their mineralization with calcium phosphate (CaP) in order to improve their suitability as materials for bone replacement. Incorporated ALP retained its bioactivity and induced formation of CaP mineral, as confirmed by SEM, FTIR, Raman spectroscopy, XRD, ICP-OES, and increases in dry mass percentage, which rose with increasing ALP concentration and incubation time in Ca-GP solution. The results demonstrate that ALP accelerates formation of thermosensitive chitosan/beta-GP hydrogels and induces their mineralization with CaP, which paves the way for applications as injectable bone replacement materials