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COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.

International audience; Bacterial lipopolysaccharides (LPS, endotoxins) are found in high amounts in the gut lumen. LPS can cross the gut barrier and pass into the blood (endotoxemia), leading to low-grade inflammation, a common scheme in metabolic diseases. Phospholipid transfer protein (PLTP) can transfer circulating LPS to plasma lipoproteins, thereby promoting its detoxification. However, the impact of PLTP on the metabolic fate and biological effects of gut-derived LPS is unknown. This study aimed to investigate the influence of PLTP on low-grade inflammation, obesity and insulin resistance in relationship with LPS intestinal translocation and metabolic endotoxemia. Wild-type (WT) mice were compared with Pltp-deficient mice (Pltp-KO) after a 4-month high-fat (HF) diet or oral administration of labeled LPS. On a HF diet, Pltp-KO mice showed increased weight gain, adiposity, insulin resistance, lipid abnormalities and inflammation, together with a higher exposure to endotoxemia compared to WT mice. After oral administration of LPS, PLTP deficiency led to increased intestinal translocation and decreased association of LPS to lipoproteins, together with an altered catabolism of triglyceride-rich lipoproteins (TRL). Our results show that PLTP, by modulating the intestinal translocation of LPS and plasma processing of TRL-bound LPS, has a major impact on low-grade inflammation and the onset of diet-induced metabolic disorders.

Diabetes is associated with an accelerated development of atherosclerosis. Specific mechanisms related to diabetes and hyperglycemia may play a role in this process. In particular, alterations of arachidonic acid (AA) metabolism have been reported. Our main goal was to investigate for differences in the concentration of LTB4 and RvD1 as well as selected cyclooxygenase-derived mediators in carotid plaques from diabetic and non-diabetic patients. We also aimed to analyze the relationship between omega 6 and omega 3 Poly-Unsaturated Fatty acids (PUFAs) content in the plaques and the concentrations of these lipid mediators.29 type 2 diabetic patients and 30 control patients admitted for surgical treatment of carotid stenosis were enrolled in the present study. Carotid plaques were harvested for in-depth lipidomic profiling.No differences for LTB4 or other lipid mediators were observed between diabetic and non-diabetic patients. RvD1 levels were below the threshold of quantification in most of the samples. A significant correlation was found between LTB4 and 5(S)-HETE levels. Omega 3 enrichment was not significantly different between control and diabetic plaques. There was a negative correlation between DHA/AA ratio and the level of 5(S)-HETE while there was a positive association with TXB2 and PGD2 concentrations.Our results does not support the hypothesis of a specific involvement of LTB4 or COX-derived mediators in diabetic atherosclerosis. The relationship between DHA enrichment and the concentrations of specific inflammatory mediators within the plaque is of interest and will need to be confirmed in larger studies.

BACKGROUND AND PURPOSE Subset of macrophages within the atheroma plaque displays a high glucose uptake activity. Nevertheless, the molecular mechanisms and the pathophysiological significance of this high glucose need remain unclear. While the role for hypoxia and hypoxia inducible factor 1α has been demonstrated, the contribution of lipid micro-environment and more specifically oxysterols is yet to be explored. EXPERIMENTAL APPROACH Human macrophages were conditioned in the presence of homogenates from human carotid plaques, and expression of genes involved in glucose metabolism was quantified. Correlative analyses between gene expression and the oxysterol composition of plaques were performed. KEY RESULTS Conditioning of human macrophages by plaque homogenates induces expression of several genes involved in glucose uptake and glycolysis including glucose transporter 1 (SLC2A1) and hexokinases 2 and 3 (HK2 and HK3). This activation is significantly correlated to the oxysterol content of the plaque samples and is associated with a significant increase in the glycolytic activity of the cells. Pharmacological inverse agonist of the oxysterol receptor liver X receptor (LXR) partially reverses the induction of glycolysis genes without affecting macrophage glycolytic activity. Chromatin immunoprecipitation analysis confirms the implication of LXR in the regulation of SLC2A1 and HK2 genes. CONCLUSION AND IMPLICATIONS While our work supports the role of oxysterols and the LXR in the modulation of macrophage metabolism in atheroma plaques, it also highlights some LXR-independent effects of plaques samples. Finally, this study identifies hexokinase 3 as a promising target in the context of atherosclerosis. LINKED ARTICLES This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

BackgroundWe have previously shown that 5-fluorouracil (5-FU) selectively kills myeloid-derived suppressor cells (MDSCs) and activates NLRP3 (NOD-leucine rich repeat and pyrin containing protein 3) inflammasome. NLRP3 activation leads to caspase-1 activation and production of IL-1β, which in turn favors secondary tumor growth. We decided to explore the effects of either a heat shock (HS) or the deficiency in heat shock protein (HSP) 70, previously shown to respectively inhibit or increase NLRP3 inflammasome activation in macrophages.MethodsCaspase-1 activation was detected in vitro in MSC-2 cells by western blot and in vivo or ex vivo in tumor and/or splenic MDSCs by flow cytometry. The effects of HS, HSP70 deficiency and anakinra (an IL-1 inhibitor) on tumor growth and mice survival were studied in C57BL/6 WT orHsp70−/−tumor-bearing mice. Finally, Th17 polarization was evaluated by qPCR (Il17a, Rorc) and angiogenic markers by qPCR (Pecam1, Eng) and immunohistochemistry (ERG).ResultsHS inhibits 5-FU-mediated caspase-1 activation in vitro and in vivo without affecting its cytotoxicity on MDSCs. Moreover, it enhances the antitumor effect of 5-FU treatment and favors mice survival. Interestingly, it is associated to a decreased Th17 and angiogenesis markers in tumors. IL-1β injection is able to bypass HS+5-FU antitumor effects. In contrast, inHsp70−/−MDSCs, 5-FU-mediated caspase-1 activation is increased in vivo and in vitro without effect on 5-FU cytotoxicity. InHsp70−/−mice, the antitumor effect of 5-FU was impeded, with an increased Th17 and angiogenesis markers in tumors. Finally, the effects of 5-FU on tumor growth can be restored by inhibiting IL-1β, using anakinra.ConclusionThis study provides evidence on the role of HSP70 in tuning 5-FU antitumor effect and suggests that HS can be used to improve 5-FU anticancer effect.

The mechanisms leading to NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome activation are still debated. It is well established that oligomerized NLRP3 interacts with apoptosis associated Speck-like protein containing a CARD domain (ASC) which polymerizes into filaments recruiting procaspase-1, leading to its activation. However, pathways triggering NLRP3 activation, such as potassium efflux, ROS production or lysosomal permeabilization, can be required or not, depending on the activators used. Here we proposed to evaluate the importance of Cathepsin B on NLRP3 inflammasome assembly and activation. Using Cathepsin B–/– BMDMs (Bone Marrow-Derived Macrophages), we first show that Cathepsin B is required for caspase-1 activation, IL-1β production and ASC speck formation, upon treatment with different types of NLRP3 activators, i.e., ATP, nigericin or crystals. Moreover, in these conditions, Cathepsin B interacts with NLRP3 at the endoplasmic reticulum (ER) level. To conclude, different NLRP3 activators lead to Cathepsin B interaction with NLRP3 at the ER level and to subsequent caspase-1 activation.

Colorectal cancer is a highly metastatic disease that could invade various distal organs and also the peritoneal cavity leading to peritoneal carcinomatosis. This is a terminal condition with poor prognosis and only palliative treatments such as cytoreductive surgery and intraperitoneal chemotherapy are proposed to some patients. However, clinicians use different parameters of treatments without any consensus. Here we decided to evaluate the effect of osmolarity in the efficacy of this procedure to kill colon cancer cells. We first show that a short exposure of platinum derivatives in hypotonic conditions is more efficient to decrease cell viability of human and murine colon cancer cells in vitro as compared to isotonic conditions. This is related to more important incorporation of platinum and the capacity of hypotonic stress to induce the copper transporter CTR1 oligomerization. Oxaliplatin in hypotonic conditions induces caspase-dependent cell death of colon cancer cells. Moreover, hypotonic conditions also modulate the capacity of oxaliplatin and cisplatin (but not carboplatin) to induce immunogenic cell death (ICD). In vivo, oxaliplatin in hypotonic conditions increases CD8+ T cell tumor infiltration and activation. Finally, in a murine peritoneal carcinomatosis model, oxaliplatin in hypotonic conditions is the only tested protocol which is able to slow down the appearance of tumor nodules and increase mice survival, while showing no effect in CD8+ T cells depleted mice or in immunodeficient mice. Altogether, our study provides new information both in vitro and in a preclinical model of peritoneal carcinomatosis, which highlights the importance of hypoosmolarity in intraperitoneal chemotherapy.

Introduction L’effet Warburg, classique dans les cancers s’observe egalement dans le glioblastome. Ce phenomene, via l’acidification du milieu tumoral favorise la migration de certaines cellules cancereuses. Objectifs Nous avons emis l’hypothese qu’une glycolyse augmentee dans le glioblastome pouvait favoriser les capacites de migration de certaines cellules tumorales pouvant etre a l’origine de la recidive tumorale. Patients et methodes La glycolyse de differentes lignees cellulaires humaines de glioblastome a ete mesuree avec l’automate Seahorse et confirmee par un dosage du lactate extracellulaire. La capacite de migration des cellules tumorales etait mesuree avec un test de cicatrisation du tapis cellulaire. L’etude de l’expression des genes impliques dans la glycolyse (PKM2 et LDHA) et le migration cellulaire (ZEB1, ZEB2, SNAIL, TWIST) a ete realisee par PCR avec ou sans traitement inhibant la glycolyse. Resultats Parmi nos lignees de glioblastomes, U118-MG presentait la glycolyse la plus elevee et LN229 l’une des glycolyses les plus faibles. U118-MG exprimait fortement les genes de la glycolyse et de la migration et avait une capacite de migration superieure a LN229 sur le test de cicatrisation du tapis cellulaire. Lorsque les cellules U118-MG etaient traitees par un inhibiteur de PKM2 (fenofibrate) ou de LDHA (acide oxamique), elle migrait moins. Discussion La glycolyse dans le glioblastome est positivement correlee a la capacite de migration des cellules tumorales. Ce mecanisme semble etre medie par le lactate comme demontre dans l’adenocarcinome du pancreas. Dans le glioblastome, des cellules aux caracteristiques souches neurales, resistantes aux therapeutiques anticancereuses vont entrainer la recidive tumorale. Inhiber la glycolyse permettrait de cibler ces cellules. Conclusion La glycolyse peut etre une cible therapeutique adjuvante interessante dans le glioblastome et pourrait potentiellement limiter la survenue de recidives dans cette tumeur tres agressive. Informations complementaires Merci aux JNLF pour le financement de l’annee recherche durant laquelle ce travail a ete realise.

Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells’ fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints’ expression.