Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce ...caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRβ is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRβ, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRβ, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.
Abstract Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only ...essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4+ T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7α,25-OHC preferentially promotes the migration of activated CD44+ CD4+ T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro-inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases.
Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the ...cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4+ and CD8+ T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
Display omitted
► Th17 cells express CD39 and CD73 ectonucleotidases ► Ectonucleotidase expression is transcriptionally regulated by STAT3 and GFI-1 ► Ectonucleotidase expression determines inflammatory vs suppressive fate of Th17 cells
Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in ...tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
Les patients présentant une obésité centrale et/ou un diabète ont un pH urinaire acide. C’est également le cas des patients présentant une lithiase idiopathique urique (AU), mais pas calcique (C). ...L’acidité urinaire des personnes obèses ou diabétiques ou AU est associée à un défaut d’ammoniurie. La stéatose rénale diminue l’ammoniurie chez le rat obèse et diabétique et celle-ci est associée à l’abondance de la graisse périrénale.
Sur une TDM, la graisse périrénale est mesurée par son épaisseur à la hauteur de la veine rénale homolatérale (épaisseur à droite+épaisseur à gauche), la graisse intra-abdominale et la graisse sous-cutanée sont mesurées par leurs surfaces en L3–L4. Seuls les hommes ayant un indice de masse corporelle (IMC)≥25kg/m2 et une lithiase définie par spectrophotométrie infrarouge participent à l’étude. Le pH urinaire, l’ammoniurie et l’excrétion nette d’acide sont mesurés sur les urines de 24h recueillies sous huile après 4jours d’un régime standardisé dont le suivi est vérifié par l’analyse des urines de 24h. L’analyse comparative est réalisée par des tests non paramétriques.
L’âge moyen est de 57±11 ans, l’IMC de 29±3kg/m2. Les apports en sel sont de 7±3g/j, en protéines de 0,9±0,1mmol/kg/j, en phosphates de 872±186mg/j sans différence entre AU et C. AU et C ont une concentration plasmatique d’acides gras libres (0,43±0,10 vs 0,37±0,07mmol/L, p=0,22) et de triglycérides (1,57±0,39 vs 1,44±0,34, p=0,36) non différente. Il y a 6 diabétiques AU versus 1C. La graisse périrénale AU est plus abondante que C (27±11 vs 18±8mm ; p=0,03) et la graisse intra-abdominale AU est plus abondante que C (277±88 vs 185±77cm2 ; p=0,01). La graisse sous-cutanée AU tend à être moins abondante que C (183±66 vs 247±115, p=0,08). Le pH urinaire AU est plus bas (5,30±0,40 vs 6,04±0,23 ; p=0,01) et le rapport ammoniurie sur excrétion urinaire nette d’acide AU tend à être plus bas que C (0,48±0,12 vs 0,67±0,09 ; p=0,07).
Nous montrons que la graisse périrénale AU est plus abondante que C et que ce résultat est corrélé à un pH urinaire plus bas pour une charge acide et des apports en phosphates alimentaires équivalents. Cette relation est déjà démontrée pour la graisse viscérale.
L’indépendance de la graisse périrénale par rapport à la graisse viscérale reste à explorer chez AU ainsi que le lien entre graisse périrénale, stéatose rénale et défaut d’ammoniurie.
Scope
Scope: It is well established that immune response and inflammation promote tumoral progression. Immune cells communicate through direct contact or through cytokine secretion, and it is the ...pro‐inflammatory status that will tip the balance toward tumor progression or anti‐tumor immunity. It is demonstrated here that a red wine extract (RWE) can decrease inflammation through its action on the inflammasome complex. This study determines whether an RWE could impact other key actors of inflammation, including T helper 17 (Th17) immune cells in particular.
Methods and results
Methods and results: Using an RWE containing 4.16 g of polyphenols/liter of wine, it is shown that RWE decreases colorectal cancer cells in vitro and induces a reduction in colorectal tumor growth associated with a decrease in tumor‐infiltrating lymphocytes in vivo. The process of T‐lymphocyte differentiation in Th17 cells is altered by RWE, as revealed by the decrease in the expression of key actors controlling this process, such as signal transducer and activator of transcription 3 and retinoid acid‐related orphan receptor γt. This disruption is associated with an inhibition of inflammatory interleukin 17 secretion.
Conclusion
The data highlights the major involvement of Th17 immune cells in the biological effects of an RWE.
Red Wine extract alters differentiation of lymphocyte T cells into pro‐inflammatory T helper 17 through an alteration of nuclear transcriptional factor, the protein RORγt. Subsequently, red wine extract disrupts pro‐inflammatory interleukin IL‐17. These events are associated in vivo with a decrease of tumor‐infiltrating lymphocytes and with a reduction of colorectal tumor growth.
Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce ...caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRbeta is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRbeta, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRbeta, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.
High-resolution manganese K-edge X-ray absorption near edge structure spectra were collected on a set of 40 Mn-bearing minerals. The pre-edge feature information (position, area) was investigated to ...extract as much as possible quantitative valence and symmetry information for manganese in various “test” and “unknown” minerals and glasses. The samples present a range of manganese symmetry environments (tetrahedral, square planar, octahedral, and cubic) and valences (II to VII). The extraction of the pre-edge information is based on a previous multiple scattering and multiplet calculations for model compounds. Using the method described in this study, a robust estimation of the manganese valence could be obtained from the pre-edge region at 5% accuracy level. This method applied to 20 “test” compounds (such as hausmannite and rancieite) and to 15 “unknown” compounds (such as axinite and birnessite) provides a quantitative estimate of the average valence of manganese in complex minerals and silicate glasses.
The aim of this study is to investigate phosphorus (P) species modifications triggered by soil genesis and mountain ecosystem development after glacial retreat using a lake sediment archive (Lake ...Anterne, North French Alps). Five lake sediment samples, representative of different stages of soil and ecosystem development, were selected for P speciation analyses. Furthermore, a sequence of current soils from the catchment was analyzed to better constrain our interpretations of the lacustrine archive. Synchrotron techniques (X-ray Fluorescence (XRF) mapping and P K-edge X-ray absorption near edge structure (XANES) spectroscopy) were applied to lake sediments, soils, and standards (mineral and organic) to distinguish between different P species. The results show that soil development during the first millennia of the Holocene triggered increased P species diversity. At the onset of the Holocene, P was present as apatite when rocks and leptosols dominated the catchment. Pedogenic processes then led to apatite dissolution and the formation of large amounts of P on metal/clay-organic complexes. P geochemistry during the main step of soil genesis (early leptosols dominated by apatite, low weathered cambisols with P mainly adsorbed on iron oxides, highly weathered podzols with large amounts of P on Al/Fe/clay organic complexes) is thus clearly recorded in lake sediments. P K-edge XANES spectroscopy is particularly relevant as qualitative method to study P species in soils and lake sediments at high spatial resolution. Such resolution is needed to reveal the diversity of small P particles and like this better characterize the P cycle and improve our understanding of ecosystem evolution.
The Lesser Antilles are a densely populated region where local populations and industrial facilities are concentrated at the coastlines, and are therefore exposed to many rapid-onset hazards such as ...hurricanes and tsunamis. However, the historical catalog of these events is too short to allow risk assessment and return period estimations, and it needs to be completed with long-term records of washover deposits in coastal sedimentary environments such as lagoons. In this study, two sediment cores were taken in March 2018 in a small coastal lagoon on Scrub Island (northeastern Caribbean). Sedimentological, geochemical, microfaunal and chronological analyses enabled us to identify 25 sandy layers resulting from high-energy-marine floods. Two of these layers were interpreted as tsunami deposits based on sedimentological (rip-up clast of the underlying cohesive substrate and internal mud laminae), and geochemical evidence. The most recent deposit is associated with the transatlantic tsunami triggered by the 1755 CE Lisbon earthquake. The older one is the thickest sandy layer recorded in the lagoon, with an age range of 1364–1469 cal. CE, as determined using 14C dating. This event was recorded in sedimentary archives of both the northern and the southern part of the Caribbean, with its large spatial extent, supporting a distant tsunamigenic origin. The 23 remaining sandy layers were interpreted as storm deposits, based on sedimentological and chronological data, with the three most recent layers being correlated with historical hurricanes. This new 1600 year-long record displays similarities with that of the Bahamas, with the periods of intense hurricane activity being in antiphase with those of the north-eastern US coast. This regional comparison may provide evidence for a latitudinal forcing of hurricane tracks through time in relation to climate fluctuations.
PDF
![Liver X receptor [beta] act...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1350-9047/small "Liver X receptor [beta] activation induces pyroptosis of human and murine colon cancer cells")
