70 research outputs found
The Unexpected Role of Neutrophils for Resolving Liver Inflammation by Transmitting MicroRNAâ223 to Macrophages
Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases
The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases
Deciphering the Immune Microenvironment on A Single Archival Formalin-Fixed Paraffin-Embedded Tissue Section by An Immediately Implementable Multiplex Fluorescence Immunostaining Protocol
Technological breakthroughs have fundamentally changed our understanding on the complexity of the tumor microenvironment at the single-cell level. Characterizing the immune cell composition in relation to spatial distribution and histological changes may provide important diagnostic and therapeutic information. Immunostaining on formalin-fixed paraffin-embedded (FFPE) tissue samples represents a widespread and simple procedure, allowing the visualization of cellular distribution and processes, on preserved tissue structure. Recent advances in microscopy and molecular biology have made multiplexing accessible, yet technically challenging. We herein describe a novel, simple and cost-effective method for a reproducible and highly flexible multiplex immunostaining on archived FFPE tissue samples, which we optimized for solid organs (e.g., liver, intestine, lung, kidney) from mice and humans. Our protocol requires limited specific equipment and reagents, making multiplexing (>12 antibodies) immediately implementable to any histology laboratory routinely performing immunostaining. Using this method on single sections and combining it with automated whole-slide image analysis, we characterize the hepatic immune microenvironment in preclinical mouse models of liver fibrosis, steatohepatitis and hepatocellular carcinoma (HCC) and on human-patient samples with chronic liver diseases. The data provide useful insights into tissue organization and immune-parenchymal cell-to-cell interactions. It also highlights the profound macrophage heterogeneity in liver across premalignant conditions and HCC
Three long period transiting giant planets from TESS
We report the discovery and orbital characterization of three new transiting
warm giant planets. These systems were initially identified as presenting
single transit events in the light curves generated from the full frame images
of the Transiting Exoplanet Survey Satellite (TESS). Follow-up radial velocity
measurements and additional light curves were used to determine the orbital
periods and confirm the planetary nature of the candidates. The planets orbit
slightly metal-rich late F- and early G-type stars. We find that TOI 4406b has
a mass of = 0.30 0.04 , a radius of = 1.00 0.02
, and a low eccentricity orbit (e=0.15 0.05) with a period of P=
30.08364 0.00005 d . TOI 2338b has a mass of = 5.98 0.20
, a radius of = 1.00 0.01 , and a highly eccentric orbit (e=
0.676 0.002 ) with a period of P= 22.65398 0.00002 d . Finally, TOI
2589b has a mass of = 3.50 0.10 , a radius of = 1.08
0.03 , and an eccentric orbit (e = 0.522 0.006 ) with a
period of P= 61.6277 0.0002 d . TOI 4406b and TOI 2338b are enriched in
metals compared to their host stars, while the structure of TOI 2589b is
consistent with having similar metal enrichment to its host star.Comment: 24 pages, 16 figures, accepted in A
A pair of Sub-Neptunes transiting the bright K-dwarf TOI-1064 characterised with CHEOPS
Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We report the discovery and characterization of a pair of sub-Neptunes transiting the bright K-dwarf TOI-1064 (TIC 79748331), initially detected in the Transiting Exoplanet Survey Satellite (TESS) photometry. To characterize the system, we performed and retrieved the CHaracterising ExOPlanets Satellite (CHEOPS), TESS, and ground-based photometry, the High Accuracy Radial velocity Planet Searcher (HARPS) high-resolution spectroscopy, and Gemini speckle imaging. We characterize the host star and determine Teff,â=4734±67Kâ , Râ=0.726±0.007Rââ , and Mâ=0.748±0.032Mââ . We present a novel detrending method based on point spread function shape-change modelling and demonstrate its suitability to correct flux variations in CHEOPS data. We confirm the planetary nature of both bodies and find that TOI-1064 b has an orbital period of Pb = 6.44387 ± 0.00003 d, a radius of Rb = 2.59 ± 0.04 Râ, and a mass of Mb=13.5+1.7â1.8 Mâ, whilst TOI-1064 c has an orbital period of Pc=12.22657+0.00005â0.00004 d, a radius of Rc = 2.65 ± 0.04 Râ, and a 3Ï upper mass limit of 8.5 Mâ. From the high-precision photometry we obtain radius uncertainties of âŒ1.6 per cent, allowing us to conduct internal structure and atmospheric escape modelling. TOI-1064 b is one of the densest, well-characterized sub-Neptunes, with a tenuous atmosphere that can be explained by the loss of a primordial envelope following migration through the protoplanetary disc. It is likely that TOI-1064 c has an extended atmosphere due to the tentative low density, however further radial velocities are needed to confirm this scenario and the similar radii, different masses nature of this system. The high-precision data and modelling of TOI-1064 b are important for planets in this region of massâradius space, and it allow us to identify a trend in bulk densityâstellar metallicity for massive sub-Neptunes that may hint at the formation of this population of planets.Publisher PDFPeer reviewe
TOI-836 : a super-Earth and mini-Neptune transiting a nearby K-dwarf
Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (T = 8.5 mag), high proper motion (âŒ200 mas yrâ1), low metallicity ([Fe/H]ââ0.28) K-dwarf with a mass of 0.68 ± 0.05 Mâ and a radius of 0.67 ± 0.01 Râ. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a 1.70 ± 0.07 Râ super-Earth in a 3.82 day orbit, placing it directly within the so-called âradius valleyâ. The outer planet, TOI-836 c, is a 2.59 ± 0.09 Râ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of 4.5 ± 0.9 Mâ, while TOI-836 c has a mass of 9.6 ± 2.6 Mâ. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet.Publisher PDFPeer reviewe
TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf
We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364)
using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (
mag), high proper motion ( mas yr), low metallicity
([Fe/H]) K-dwarf with a mass of M and a
radius of R. We obtain photometric follow-up
observations with a variety of facilities, and we use these data-sets to
determine that the inner planet, TOI-836 b, is a R
super-Earth in a 3.82 day orbit, placing it directly within the so-called
'radius valley'. The outer planet, TOI-836 c, is a R
mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that
TOI-836 b has a mass of M , while TOI-836 c has a mass
of M. Photometric observations show Transit Timing
Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are
no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by
an undetected exterior planet
Influence of IL-17 response in liver pathophysiology
La persistance et la rĂ©currence de la rĂ©ponse inflammatoire dans le foie est la principale cause de dĂ©veloppement des lĂ©sions hĂ©patiques et de ses complications. Cette rĂ©ponse immune est caractĂ©risĂ©e par le recrutement de cellules inflammatoires, notamment de monocytes/macrophages et de lymphocytes. Elle est aussi impliquĂ©e d'une part dans le dĂ©veloppement de la fibrose en activant les cellules fibrogĂ©niques du foie, et d'autre part dans les mĂ©canismes de rĂ©gĂ©nĂ©ration. RĂ©cemment, la prĂ©sence d'une sous-population de lymphocytes T appelĂ©s Th17 a Ă©tĂ© identifiĂ©e dans de nombreuses pathologies hĂ©patiques incluant la fibrose. Leur prĂ©sence a Ă©galement Ă©tĂ© observĂ©e lors de la rĂ©gĂ©nĂ©ration hĂ©patique Ă partir de cellules progĂ©nitrices. Ces lymphocytes Th17 sont caractĂ©risĂ©s principalement par la production de deux cytokines l'IL-17 et l'IL-22. Alors que le rĂŽle de l'IL-22 a Ă©tĂ© rĂ©cemment caractĂ©risĂ© dans la fibrose et la rĂ©gĂ©nĂ©ration hĂ©patique, le rĂŽle de l'IL-17 nĂ©cessitait d'ĂȘtre dĂ©fini.Les objectifs de ma thĂšse ont donc Ă©tĂ© d'Ă©tudier le rĂŽle et la rĂ©gulation de l'IL-17 dans 1) les mĂ©canismes de dĂ©veloppement de la fibrose, et 2) son impact sur la rĂ©gĂ©nĂ©ration hĂ©patique Ă partir de cellules progĂ©nitrices.1) L'Ă©quipe a dĂ©montrĂ© l'implication du systĂšme endocannabinoĂŻde dans les maladies chroniques du foie. Ce systĂšme est composĂ© de deux types de rĂ©cepteurs, CB1 et CB2, couplĂ©s aux protĂ©ines G, et de ligands lipidiques endogĂšnes. Alors que CB1 est majoritairement exprimĂ© dans le cerveau et faiblement dans les tissus pĂ©riphĂ©riques, CB2 est trĂšs fortement exprimĂ© par les cellules immunitaires et prĂ©sente en gĂ©nĂ©ral des propriĂ©tĂ©s anti-inflammatoires. Notre hypothĂšse a donc Ă©tĂ© que l'activation du rĂ©cepteur CB2, exprimĂ© par les lymphocytes T rĂ©gulerait nĂ©gativement la rĂ©ponse de type Th17 et le dĂ©veloppement de la fibrose hĂ©patique. Dans un modĂšle murin de fibrose induite par la ligature de la voie biliaire principale, nous avons montrĂ© que des souris CB2-/- dĂ©veloppent une fibrose plus importante associĂ©e Ă une rĂ©ponse inflammatoire de type Th17 augmentĂ©e par rapport Ă des souris sauvages. De plus, l'inhibition de la production de l'IL-17 chez ces souris CB2-/- Ă l'aide d'un inhibiteur de la diffĂ©renciation Th17 (la digoxine), permet de rĂ©duire le dĂ©veloppement de la fibrose. In vitro, l'activation du rĂ©cepteur CB2 sur les lymphocytes Th17 par un agoniste sĂ©lectif, le JWH-133, diminue leur capacitĂ© Ă produire l'IL-17. Par ailleurs, nous avons montrĂ© par immunocyto-fluorescence, que l'activation de CB2 inhibe la production de l'IL-17 par une voie STAT5-dĂ©pendante. Ainsi, l'immuno-modulation de la rĂ©ponse inflammatoire associĂ©e Ă la fibrose reprĂ©sente une stratĂ©gie anti-fibrosante prometteuse.2) L'infiltration de ces cellules Th17 a Ă©galement Ă©tĂ© observĂ©e dans de nombreuses hĂ©patopathies associĂ©es Ă une accumulation de cellules progĂ©nitrices intra-hĂ©patiques (CPIH), appelĂ©es cellules ovales chez les rongeurs. La deuxiĂšme partie de ma thĂšse a donc consistĂ© en l'Ă©tude du rĂŽle de l'IL-17 dans la rĂ©gĂ©nĂ©ration du foie Ă partir de CPIH. Dans un modĂšle murin de rĂ©gĂ©nĂ©ration hĂ©patique Ă partir de CPIH induit par un rĂ©gime dĂ©ficient en choline, et supplĂ©mentĂ© en Ă©thionine (CDE), nous avons montrĂ© que des souris invalidĂ©es pour l'IL-17 (IL-17-/-) prĂ©sentent une diminution du nombre de CPIH CK19+, par rapport aux souris sauvages. L'invalidation de l'IL-17-/- a Ă©galement Ă©tĂ© associĂ©e Ă une rĂ©duction du recrutement macrophagique et de la rĂ©ponse pro-inflammatoire incluant l'IL-6, l'IL-1b et l'IL-27. Parmi ces cytokines, nous avons identifiĂ© l'IL-27 comme Ă©tant un facteur clĂ© dans la diffĂ©renciation des CPIH. In vitro, nous avons Ă©galement montrĂ© que la production de l'IL-27 est induite par la stimulation des macrophages par l'IL-17. Ainsi, nos rĂ©sultats rĂ©vĂšlent que l'action combinĂ©e de l'IL-17 et de l'IL-27 orchestre la rĂ©gĂ©nĂ©ration du foie Ă partir de CPIH en favorisant leur prolifĂ©ration et leur diffĂ©renciation en hĂ©patocytes, respectivement.Persistence and recurrence of inflammatory response in the liver is the major cause of liver damage and its complications. This immune response is characterized by inflammatory cell recruitment, in particular monocytes / macrophages and lymphocytes. It has also been implicated in fibrosis development by activating liver fibrogenic cells, and also in regeneration mechanisms. Recently, a sub population of T lymphocytes called Th17 has been identified in numerous liver pathologies including fibrosis. These cells have also been observed in regenerating livers from progenitor cells. Th17 lymphocytes are mainly characterized by the production of two cytokines, namely IL-17 and IL-22. While the role of IL-22 has been recently described in liver fibrosis and regeneration, the role of IL-17 remained to be studied.The aims of my thesis were to study the role and the regulation of IL-17 in 1) fibrosis development, and 2) its impact on liver regeneration from progenitor cells.1) Our team has demonstrated the implication of the endocannabinoid system in chronic liver disease. This system is composed of two G-protein coupled receptors, CB1 and CB2, and their endogenous lipidic ligands. While CB1 is mainly expressed in the brain and slightly in peripheral tissues, CB2 is strongly expressed by immune cells and generally displays anti-inflammatory properties. Our hypothesis was that CB2 receptor activation, expressed by T lymphocytes, would negatively regulate Th17 response and liver fibrosis development. In a murine fibrosis model induced by bile duct ligation and section, we have showed that CB2-/- mice have an enhanced fibrosis associated with an increased Th17 inflammatory response as compared to wild-type animals. Additionally, IL-17 production inhibition in these CB2-/- mice with an inhibitor of Th17 differentiation (digoxin), reduced fibrosis development. In vitro, CB2 receptor activation on Th17 lymphocytes by a selective agonist, JWH-133, diminished their ability to produce IL-17. Moreover, we demonstrated by immunocyto-fluorescence, that CB2 activation inhibits IL-17 production in a STAT5-dependent manner. Thus, the modulation of the inflammatory response associated with fibrosis is a promising strategy against fibrosis.2) Th17 cell infiltration has also been observed in liver disease associated with liver progenitor cell (LPC) accumulation, called oval cells in rodents. The second part of my thesis was aimed to study IL-17 role in liver regeneration from LPC. In a murine model of liver regeneration from LPC induced by a choline deficient and Ă©thionine supplemented diet (CDE), we have demonstrated that IL-17 deficient mice (IL-17-/-) have a reduced number of CK19+ LPC as compared to wild-type animals. IL-17 deficiency was also associated with a decrease in macrophage recruitment and reduced pro-inflammatory response including IL-6, IL-1b and IL-27. Among these cytokines, we identified IL-27 as a key factor in LPC differentiation. In vitro, we also showed that IL-27 production is induced after IL-17-induced macrophage activation. Thereby our results revealed that the combined action of IL-17 and IL-27 leads to LPC driven liver regeneration by enhancing their proliferation and their differentiation towards hepatocytes, respectively
Ătude d'opportunitĂ© pour le dĂ©ploiement d'un PĂŽle Cirque permanent dans la ville de Biscarrosse (Landes)
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