Targeting IL-6 trans-signalling by sgp130Fc attenuates severity in SARS-CoV-2 -infected mice and reduces endotheliopathy.

Background: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects.

MAFB shapes human monocyte-derived macrophage response to SARS-CoV-2 and controls severe COVID-19 biomarker expression.

Monocyte-derived macrophages, the major source of pathogenic macrophages in COVID-19, are oppositely instructed by macrophage CSF (M-CSF) or granulocyte macrophage CSF (GM-CSF), which promote the generation of antiinflammatory/immunosuppressive MAFB+ (M-MØ) or proinflammatory macrophages (GM-MØ), respectively. The transcriptional profile of prevailing macrophage subsets in severe COVID-19 led us to hypothesize that MAFB shapes the transcriptome of pulmonary macrophages driving severe COVID-19 pathogenesis. We have now assessed the role of MAFB in the response of monocyte-derived macrophages to SARS-CoV-2 through genetic and pharmacological approaches, and we demonstrate that MAFB regulated the expression of the genes that define pulmonary pathogenic macrophages in severe COVID-19.

Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice.

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases.

Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19.

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration.

The Gene Signature of Activated M-CSF-Primed Human Monocyte-Derived Macrophages Is IL-10-Dependent.

During inflammatory responses, monocytes are recruited into inflamed tissues, where they become monocyte-derived macrophages and acquire pro-inflammatory and tissue-damaging effects in response to the surrounding environment. In fact, monocyte-derived macrophage subsets are major pathogenic cells in inflammatory pathologies. Strikingly, the transcriptome of pathogenic monocyte-derived macrophage subsets resembles the gene profile of macrophage colony-stimulating factor (M-CSF)-primed monocyte-derived human macrophages (M-MØ).

New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology.

IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease.

Physiopathology of Lifestyle Interventions in Non-Alcoholic Fatty Liver Disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years. Diet and exercise interventions are the first-line treatment options, with weight loss via a hypocaloric diet being the most important therapeutic target in NAFLD. However, most NAFLD patients are not able to achieve such weight loss.

Cardiotrophin-1 contributes to metabolic adaptations through the regulation of lipid metabolism and to the fasting-induced fatty acid mobilization.

It is becoming clear that several human pathologies are caused by altered metabolic adaptations. During liver development, there are physiological changes, from the predominant utilization of glucose (fetal life) to the use of lipids (postnatal life). Fasting is another physiological stress that elicits well-known metabolic adjustments.

Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.

Macrophages play a central role in tissue remodeling, repair, and resolution of inflammation. Macrophage polarization to M1 or M2 activation status may determine the progression or resolution of the inflammatory response. We have previously reported that cardiotrophin-1 (CT-1) displays both cytoprotective and metabolic activities.

Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.

Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects.

Cardiotrophin-1 Regulates Adipokine Production in 3T3-L1 Adipocytes and Adipose Tissue From Obese Mice.

Cardiotrophin-1 (CT-1) belongs to the IL-6 family of cytokines. Previous studies of our group revealed that CT-1 is a key regulator of glucose and lipid metabolism. The aim of the present study was to analyze the in vitro and in vivo effects of CT-1 on the production of several adipokines involved in body weight regulation, nutrient metabolism, and inflammation.

Cardiotrophin-1: A multifaceted cytokine.

Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines that have pleiotropic functions on different tissues and cell types. Although many effects of CT-1 have been described on the heart, there is an extensive research showing important protective effects in other organs such as liver, kidney or nervous system. Recently, several studies have pointed out that CT-1 might also play a key role in the regulation of body weight and intermediate metabolism.

Cardiotrophin-1 stimulates lipolysis through the regulation of main adipose tissue lipases.

Cardiotrophin-1 (CT-1) is a cytokine with antiobesity properties and with a role in lipid metabolism regulation and adipose tissue function. The aim of this study was to analyze the molecular mechanisms involved in the lipolytic actions of CT-1 in adipocytes. Recombinant CT-1 (rCT-1) effects on the main proteins and signaling pathways involved in the regulation of lipolysis were evaluated in 3T3-L1 adipocytes and in mice.

Cardiotrophin-1 eliminates hepatic steatosis in obese mice by mechanisms involving AMPK activation.

Background & Aims: Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD).

Methods: rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice.

Decreased cardiotrophin-1 levels are associated with a lower risk of developing the metabolic syndrome in overweight/obese children after a weight loss program.

Objective: Cardiotrophin-1 (CT-1) shares some similarities with other cytokines, and participates in the control of energy metabolism. Higher circulating levels are observed in obese humans, but little information is gathered in weight loss (WL) programs. Therefore, we aimed to investigate the association of serum CT-1 levels with metabolic variables and the risk of developing metabolic syndrome (MetS) after a WL program in overweight/obese children.

Role of cardiotrophin-1 in obesity and insulin resistance.

Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. In a recent study we examined the metabolic features of null mice and the effects on body composition, glucose and lipid metabolism of acute and chronic administration of recombinant CT-1. Our data revealed that CT-1 is a key regulator of energy metabolism with potential applications in the treatment of obesity and the metabolic syndrome.

Serotonin skews human macrophage polarization through HTR2B and HTR7.

Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization-associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2).

Cardiotrophin-1 determines liver engraftment of syngenic colon carcinoma cells through an immune system-mediated mechanism.

Cardiotrophin-1 (CT-1/CTF1) is a member of the interleukin-6 (IL-6) family of cytokines that stimulates STAT-3 phosphorylation in cells bearing the cognate receptor. We report that Ctf1(-/-) mice (hereby referred to as CT-1(-/-) mice) are resistant to the hepatic engraftment of MC38 colon carcinoma cells, while these cells engraft normally in the mouse subcutaneous tissue. Tumor intake in the liver could be enhanced by the systemic delivery of a recombinant adenovirus encoding CT-1, which also partly rescued the resistance of CT-1(-/-) mice to the hepatic engraftment of MC38 cells.

Cardiotrophin-1 promotes a high survival rate in rabbits with lethal fulminant hepatitis of viral origin.

Rabbit hemorrhagic disease virus (RHDV) causes lethal fulminant hepatitis closely resembling acute liver failure (ALF) in humans. In this study, we investigated whether cardiotrophin-1 (CT-1), a cytokine with hepatoprotective properties, could attenuate liver damage and prolong survival in virus-induced ALF. Twenty-four rabbits were infected with 2 × 10(4) hemagglutination units of RHDV.

Cardiotrophin-1 is a key regulator of glucose and lipid metabolism.

Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. We observed that ct-1(-/-) mice develop mature-onset obesity, insulin resistance, and hypercholesterolemia despite reduced calorie intake. Decreased energy expenditure preceded and accompanied the development of obesity.

Eicosapentaenoic acid inhibits tumour necrosis factor-α-induced lipolysis in murine cultured adipocytes.

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid with beneficial effects in obesity and insulin resistance. High levels of proinflammatory cytokine tumour necrosis factor-α (TNF-α) in obesity promote lipolysis in adipocytes, leading to the development of insulin resistance. Thus, the aims of the present study were to analyze the potential antilipolytic properties of EPA on cytokine-induced lipolysis and to investigate the possible mechanisms involved.