BACKGROUND & AIMS:The circadian clock dictates time-of-day dependent gene, protein expression, and metabolite levels to ensure liver homeostasis. Circadian misalignment is implicated in the development of various metabolic disorders, but its contribution to the progression of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) toward Metabolic dysfunction-Associated Steatohepatitis (MASH) remains poorly understood. Here, we aimed to dissect the role of the circadian clock in MASH development. METHODS:Using an environmental model of chronic circadian misalignment (n=6-12/group), combined with metabolic and immune phenotyping, single nuclei transcriptomics and lipidomic profiling, we investigated the role of the clock in MASLD development and hepatic inflammation. To dissect the specific contribution of the immune clock, we used a genetic model overexpressing the clock component Rev-erbα in myeloid cells (n=3-5/group). RESULTS:Chronic circadian misalignment combined with a high-fat, high-sucrose, cholesterol-enriched (HFHSC) diet markedly amplified hepatic inflammation, characterized by the upregulation of pro-inflammatory genes (p<0.01) and increased immune cell infiltration, including the expansion of hepatic lipid-associated macrophages (hLAMs) (p<0.0001). This heightened inflammatory response promoted fibrotic deposition (p<0.0001). Although circadian misalignment did not worsen glucose intolerance or hepatic steatosis, it altered hepatic metabolic gene expression profile, indicating a broad reprogramming of immune and metabolic pathways. Conversely, myeloid-specific Rev-erbα overexpression attenuated hepatic inflammation in HFHSC-fed mice (p<0.05). CONCLUSIONS:The circadian clock controls both hepatic fatty acid profile and inflammatory process, and its misalignment aggravates MASLD by increasing liver inflammation and fibrosis. Targeting circadian regulators such as Rev-erbα in myeloid cells may offer a promising therapeutic avenue for controlling liver inflammation in MASLD. IMPACT AND IMPLICATIONS:By combining environmental and genetic approaches, this study highlights the central role of the circadian clock in regulating hepatic inflammation during MASLD progression. These findings underscore the importance of considering biological rhythms in the prevention of chronic metabolic diseases and support the potential of circadian clock-targeted strategies as a novel therapeutic avenue.

Acute community-acquired pneumonia (CAP) is a leading cause of infection-related mortality worldwide. Endotoxemia, characterized by elevated plasma lipopolysaccharide (LPS), is a key driver of inflammation and thrombosis in Gram-negative sepsis and has been suggested to occur in severe pneumonia, irrespective of etiology. However, current immunoassays for LPS quantification lack sensitivity and specificity. We aimed to quantify plasma LPS in severe CAP patients, including COVID-19, using a validated mass spectrometry method, and to explore associations with immune activation, coagulation, gut translocation, and clinical outcomes. In this prospective ancillary study of the LYMPHONIE cohort, we included 34 non-COVID-19 severe CAP (sCAP), 34 severe COVID-19 (sCOVID-19) and 34 matched healthy volunteers. Plasma LPS was measured by LC–MS/MS detecting 3-hydroxy fatty acids of lipid A. Clinical data, immune biomarkers, coagulation biomarkers, and gut injury markers were measured. Unexpectedly, median plasma LPS concentrations were significantly lower in sCAP patients (724 pmol/ml in sCAP; 750 pmol/ml in sCOVID-19) compared to healthy volunteers (1009 pmol/ml, p < 0.001). LPS levels did not correlate with severity scores or mortality. Low positive correlations were observed between LPS and markers of endothelial activation (sVCAM-1) and coagulation (D-dimer). However, patients with high LPS showed no increased risk of thrombotic or cardiovascular events. Using a highly specific LC–MS/MS method, we found no evidence of increased circulating LPS in severe pneumonia patients, challenging the hypothesis of gut-derived endotoxemia as a major contributor to systemic inflammation in severe CAP, including COVID-19. Take-home message Using a highly specific mass-spectrometry assay, we found no evidence of elevated circulating lipopolysaccharide in severe community-acquired pneumonia, including COVID-19. These findings challenge the concept that gut-derived endotoxemia is a major driver of systemic inflammation in severe pneumonia. Tweet Mass spectrometry reveals no rise in plasma LPS in severe pneumonia or COVID-19, questioning gut endotoxemia’s role in inflammation.

BACKGROUNDS:In patients with cardiac surgery under cardiopulmonary bypass (CPB), postoperative inflammation is a driver of adverse outcomes. Endotoxaemia is one of the factors thought to trigger this inflammatory response. The mechanism behind high endotoxin activity (increased translocation vs. reduced inactivation capacity) has never been elucidated and may imply different therapeutic candidates. OBJECTIVES:We aimed to evaluate, in patients with cardiac surgery with prolonged CPB, mechanisms and consequences of endotoxaemia and the efficacy of haemo-adsorption to reduce the endotoxin burden. DESIGN:Ancillary analysis of a randomised controlled trial. Patients scheduled for cardiac surgery with prolonged CPB were assigned to receive either intra-operative haemo-adsorption or standard of care. Endotoxin mass and activity were measured before surgery, at the end of CPB, 6, 24 and 48 h after the end of surgery. SETTING:Operating room, Amiens University Hospital. PATIENTS:Adults scheduled for cardiac surgery under CPB with an expected CPB time more than 90 min. INTERVENTION:Patients were randomised to receive either haemo-adsorption or standard care during CPB. MAIN OUTCOME MEASURES:Endotoxin activity. RESULTS:Two hundred and ninety-five samples from 66 patients were analysed. Following CPB, we observed a reduction in endotoxin mass accompanied by a relative increase in endotoxin activity. High postoperative endotoxin activity was associated with intra-operative dobutamine requirement, increased postoperative inflammatory biomarkers and organ injury. Endotoxin plasma concentration and activity were not lower in patients treated with haemo-adsoprtion. CONCLUSION:The capacity of individuals to inactivate endotoxin rather than raw endotoxin mass (i.e. Quantity) seemed to be a determinant of endotoxin noxious effect in cardiac surgery and CBP. Haemo-adsorption was not associated with a reduction of endotoxin plasma mass or activity in patients with cardiac surgery under CPB. TRIAL REGISTRATION:ClinicalTrials.gov, NCT04201119NCT04201119.

BackgroundImmune dysregulation is strongly involved in acute myocardial infarction (AMI), driving sustained inflammation and myocardial damage. A better understanding of the immune cell response to AMI is needed, beyond neutrophil and monocyte counts. Cell Population Data (CPD) analysis, including granularity (SSC), size (FSC), activation (SFL), and heterogeneity indices, offers deeper insights into the dynamics of leukocyte populations.ObjectiveOur goal was to investigate CPD as prognostic biomarkers for cardiovascular (CV) mortality after AMI and to assess their links to inflammatory and lipid markers.MethodsSamples from 572 patients with AMI were collected at the admission in the cardiology intensive care unit. In addition to routine blood tests, CPD was acquired on an automated haematology analyser. Plasma inflammatory markers, as well as detailed fatty acid profiles, were also measured. A one-year follow-up was then conducted to assess CV mortality.ResultsNeutrophil, monocyte, and immature granulocyte (IG) counts and neutrophil heterogeneity of fluorescence (NE-WY) were associated with CV deaths, myocardial infarction (MI), and inflammatory biomarkers such as hs-CRP and IL-6. On the opposite, lymphocyte count was inversely associated with CV death and inflammatory markers. Monocyte count and CPD were correlated with saturated fatty acids, especially palmitic acid.ConclusionOur findings demonstrate that CPD, particularly parameters related to neutrophils and monocytes, are robustly linked to inflammation and the occurrence of CV mortality. Importantly, these CPD—readily accessible through standard clinical haematology analysers—hold significant potential as predictive biomarkers for clinicians to assess cardiovascular risk in routine practice.

Essential fatty acid metabolism in myeloid cells plays a critical but underexplored role in immune function. Here, we demonstrate that simultaneous inactivation of two key enzymes involved in macrophage polyunsaturated fatty acid (PUFA) metabolism-ELOVL5, which elongates long-chain PUFAs, and LPCAT3, which incorporates them into phospholipids-disrupts membrane organization by promoting the formation of cholesterol-enriched domains. This increases macrophage sensitivity to cytotoxic oxysterols and leads to more vulnerable atherosclerotic plaques with enlarged necrotic cores in a mouse model of atherosclerosis. In humans, analysis of 187 carotid plaques reveals a positive correlation between LPCAT3/ELOVL5-generated phospholipids-including arachidonate (C20:4 n-6)-containing ether lipids-and more stable plaque profiles. Additionally, Mendelian randomization analysis supports a causal relationship between LPCAT3 expression and reduced risk of ischemic stroke. Our findings uncover a regulatory circuit essential for PUFA-containing phospholipid generation in macrophages, positioning PUFA-containing ether lipids as promising biomarkers and therapeutic targets.

Aims The efficacy of omega-3 fatty acid supplementation in cardiovascular prevention remains debated. Observational data suggest that individual fatty acids may have distinct prognostic value after acute myocardial infarction (AMI). This study aims to analyse the association of plasma fatty acid (FA) levels including eicosapentaenoic acid (EPA) and the EPA/docosahexaenoic acid (DHA) ratio at the time of AMI with 1-year cardiovascular (CV) mortality. Methods and results This prospective study included 572 patients hospitalized for AMI. Plasma FA levels were measured using gas chromatography coupled with mass spectrometry. The associations between FA profiles and CV mortality at 1-year follow-up were analysed using Cox proportional hazards models. At follow-up, 29 deaths were cardiovascular-related. Patients who died had lower relative levels of EPA [0.47% (0.28-0.73) vs. 0.73% (0.52-1.02), P < 0.001], a lower EPA/DHA ratio [0.33 (0.22-0.43) vs. 0.44 (0.33-0.61), P < 0.001], and more elevated levels of inflammatory biomarkers, including hs-CRP and interleukin-1 beta. In contrast, DHA levels were not associated with CV mortality. In multivariate analysis, the EPA/DHA ratio was associated with lower CV mortality, even after adjustment for confounding factors including GRACE risk score, left ventricular ejection fraction, and inflammatory biomarkers. Conclusion Our study demonstrates that higher plasma levels of EPA and EPA/DHA ratio are associated with lower CV mortality one year after AMI.

Most severe cardiogenic shock requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO). The OXIRIS filter, has shown potential in reducing lipopolysaccharide (LPS) levels. Our objective was to compare the efficacy of the OXIRIS filter versus the ST-150 filter in reducing LPS plasma concentration. We hypothesized that the OXIRIS filter would reduce the endotoxin burden. We conducted an open-label randomized prospective study in the cardiac intensive care unit of Dijon University Hospital. Forty patients with refractory cardiogenic shock requiring VA-ECMO and renal replacement therapy (RRT) were randomized to receive either OXIRIS filter or ST-150 filter. Blood samples were collected at multiple time points. The primary outcome was LPS mass (measured 24 h after the initiation of treatment). Secondary outcomes included LPS activity, cytokine levels, and clinical outcomes. 20 patients were allocated to each group and analyzed. LPS plasma concentrations were not different between the OXIRIS filter and ST-150 filter groups at H24 (599 pmol/ml of esterified 3-OH fatty acids [450;734] vs 520 [456;835], p = 0.983) or when analyzing all time-points by linear mixed modelling (538 [469;723] vs 507 [434;671] at H26, 576 [513;614] vs 624 [503;724] at H48 and 632 [513;660] vs 586 [538;776] at H72, p = 0.882). No significant between groups differences were found in LPS activity, inflammation markers (IL-6, TNF-α, IL-10, MCP-1), SOFA scores, VIS scores, or 28-day mortality (13 (65

BackgroundElevated plasma levels of glucagon-like peptide-1 (GLP-1) have been associated with poor clinical outcome in patients with sepsis. This study investigated the association between GLP-1 levels, and survival at 90 days in a large cohort of critically ill patients.MethodsAll patients aged ≥ 18 years admitted to the intensive care unit (ICU) in a large university hospital, and receiving ≥1 life support therapy for organ failure were eligible for inclusion. Plasma samples were taken within 24h of ICU admission. We measured GLP-1 using a commercial ELISA kit. Cumulative probability of death at 90 days (D90) was plotted using the Kaplan-Meier method by quartiles of GLP-1. The effect of GLP-1 quartile on D90 survival was analyzed using a Cox proportional hazards model.ResultsA total of 507 patients had GLP-1 dosage; mean age 64.5 ± 14.5 years; 179 (35.3%) women. GLP-1 levels ranged from 0.03 to 129.2 (median 7.3[IQR:3.3;19.1]). Higher mean age, SOFA, SAPS II, and LPS 3HM were found in patients with higher GLP-1 quartile by univariate analysis. Overall, 229 patients (45.2%) died within 90 days. The cumulative probability of death was significantly associated with GLP-1 quartile (p log rank<0.0001). After adjustment for age, SOFA, renal replacement therapy and vasopressor treatment, a significantly increased risk was observed only for patients with the highest quartile of GLP-1 (adjusted hazard ratio 1.65 [1.06; 2.56] for 4th vs 1st quartile of GLP-1).ConclusionAfter adjusting for demographic and clinical characteristics, only the highest quartile of GLP-1 remained independently associated with an increased risk of death at 90 days after admission to ICU.

Background and aimsCell death plays a central role in atheroma plaque progression and aggravation. This study investigates the role of caspase-8 in regulating macrophage cell death modalities, specifically apoptosis and necroptosis, within atheroma plaques.MethodsBone marrow from caspase-8-deficient (Casp8komac) and cohoused wildtype littermates were transplanted in atherosclerosis-prone Ldlr-/- recipient mice fed with a proatherogenic diet. Aortic plaque development, necrotic core formation, and cell death were analyzed through histological and biochemical assays. In vitro investigation of macrophages exposed to atherogenic stimuli assessed the effects of caspase-8 inhibition on apoptotic and necroptotic pathways.ResultsDespite lower plasma cholesterol levels and reduced number of inflammatory monocytes, caspase-8-deficient mice exhibited more pronounced atherosclerotic lesions with enlarged necrotic cores and an increased number of dead cells. In vitro, in macrophages exposed to oxidized LDL or oxysterols, the inhibition of caspase-8 revealed a shift from apoptosis to necroptosis as confirmed by increased phosphorylation of MLKL along with decreased cleavage of caspase-3 and -7.Discussion and perspectivesThe study highlights the role of caspase-8 in atherosclerosis in tuning the balance between apoptosis and necroptosis. Caspase-8 inhibition leads to a switch towards necroptosis and accumulation of dead cell corpses that contributes to enhanced plaque severity. These findings suggest that reducing caspase-8-regulated necroptosis and necrosis in macrophages could represent a therapeutic strategy to stabilize plaques and reduce cardiovascular risk.

AIMS:Low plasma high-density lipoprotein (HDL)-cholesterol levels are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD), potentially reflecting impaired antiatherogenic HDL functions. These latter are strongly influenced by the HDL phospholipidome, which is frequently altered in ASCVD patients. Several studies reported that plasma levels of phosphatidylethanolamine (PE) species, particularly PE (36:5), were positively associated with ASCVD, but the underlying mechanisms remain unclear. Plasma PE (36:5) exists as eicosapentaenoic (EPA)-PE and arachidonic acid (ARA)-PE, with the latter predominating in ASCVD. This study investigated whether the association of PE (36:5) with ASCVD might result from an impairment of the antiatherogenic functions of HDL. METHODS AND RESULTS:Total PE and PE (36:5) content of large HDL isolated from 86 women with metabolic syndrome was positively associated with carotid intima-media thickness in multivariate regression analysis adjusted for traditional risk factors. In TgCETP x Ldlr-/- mice fed a high-cholesterol diet, the atherosclerotic plaque size was greater when reconstituted HDL (rHDL) containing ARA-PE was injected retro-orbitally, compared with injection of control rHDL containing only phosphatidylcholine (PC). In vitro, PE rHDL showed reduced cholesterol efflux capacity and impaired anti-inflammatory activity in THP-1 macrophages, together with diminished anti-oxidative activity against LDL oxidation compared to control rHDL. Strikingly, ARA-PE rHDL profoundly weakened of the HDL functions, while EPA-PE counteracted the ARA-PE-induced dysfunction and potentiated the functionality of rHDL. CONCLUSIONS:This study reveals a causal link between PE species, particularly ARA-PE, and HDL dysfunction, contributing to atherosclerosis. EPA-PE can restore HDL function, supporting the therapeutic potential of EPA reducing ASCVD risk.

BACKGROUND:The efficacy of omega-3 fatty acid supplementation in cardiovascular prevention remains debated. Observational data suggest that individual fatty acids may have distinct prognostic value after acute myocardial infarction (AMI). OBJECTIVES:To analyze the association of plasma fatty acid (FA) levels including eicosapentaenoic acid (EPA) and the EPA/docosahexaenoic acid (DHA) ratio at the time of AMI with one-year cardiovascular (CV) mortality. METHODS AND RESULTS:This prospective study included 572 patients hospitalized for AMI. Plasma FA levels were measured using gas chromatography coupled with mass spectrometry. The associations between FA profiles and CV mortality at one-year follow-up were analyzed using Cox proportional hazards models. At follow-up, 29 deaths were cardiovascular-related. Patients who died had lower relative levels of EPA (0.47% (0.28-0.73) vs. 0.73% (0.52-1.02), p<0.001), a lower EPA/DHA ratio (0.33 (0.22-0.43) vs. 0.44 (0.33-0.61) p<0.001), and more elevated levels of inflammatory biomarkers, including hs-CRP and interleukin-1β. In contrast, DHA levels were not associated with CV mortality. In multivariate analysis, the EPA/DHA ratio was associated with lower CV mortality, even after adjustment for confounding factors including GRACE risk score, left ventricular ejection fraction, and inflammatory biomarkers. CONCLUSION:Our study demonstrates that higher plasma levels of EPA and EPA/DHA ratio are associated with lower CV mortality one year after AMI.

IntroductionLipopolysaccharide (LPS) is a major virulence factor during both meningococcal and Haemophilus influenzae meningitis. Pneumococcus does not produce LPS but could be responsible for bacterial digestive translocation as a consequence of sepsis. We addressed this question in the context of pneumococcal meningitis.MethodsA cross-sectional study on 24 patients with pneumococcal meningitis (20 (83%) admitted in intensive care unit, 4 (17%) with septic shock) and 34 prospectively-enrolled healthy volunteers. Interleukin 6 and C-reactive proteins plasma concentrations were measured as markers of systemic inflammation. Endotoxemia was measured using mass spectrometry (LC-MS/MS) for detection of molecules bound to the lipid A, namely 3-OH fatty acids.ResultsMeningitis patients had significantly higher levels of plasma C-reactive protein (237 (74-373) vs. 2 (2-2) mg/l, p < 0.001 and interleukin 6 (43 (13-128) vs. 4.6 (4.6-16.6) pg/ml; p < 0.001) than healthy volunteers. However, we observed no significant difference in plasma lipopolysaccharide concentrations between patients and healthy volunteers (674 (554-896) vs. 668 (623-777) pmol/ml; p = 0.546).ConclusionsOur results suggest that LPS is not a key determinant of the excessive inflammation associated with severe forms of pneumococcal meningitis.

BACKGROUND:The high-density lipoprotein (HDL) and the phospholipid transfer protein (PLTP) have been demonstrated to enhance endotoxin elimination and inactivation in animal models of sepsis. This study aimed to confirm such a role in patients presenting with abdominal sepsis undergoing emergent surgery and explore the relationships between HDL, PLTP and the lipopolysaccharide (LPS) burden (mass and activity). METHODS:Patients operated for abdominal sepsis were prospectively included in the study. Blood samples were obtained before surgery, at the end of the operation (H0), 4 h (H4) and 24 h (H24) later. Peritoneal fluid was also sampled. HDL cholesterol, LDL cholesterol, PLTP activity, LPS mass and activity were measured. RESULTS:Twenty-seven patients were included. At H0, LPS mass was mostly measured in the lipoprotein fractions (46% [23; 58] in HDL and 36% [29; 54] in LDL). Overall, LPS mass and LPS activity did not decrease in the 24 h following admission to the ICU. Both HDLc concentrations and PLTP activity were associated with increased H4-LPS elimination (drop in LPS concentration, -3% [-26;10] vs. 29% [13;52], p < 0.01 and -2% [-15;10] vs. 20% [8:52], p = 0.03, respectively). Increased H4-LPS elimination was associated with reduced inflammation (plasma cytokine concentration) and mortality. High HDL cholesterol was associated with reduced mortality but not with inflammation. CONCLUSION:Our data support the role of HDL and PLTP in the elimination of LPS during human peritonitis with sepsis. Increased H4-LPS elimination was associated with reduced inflammation and lower mortality. CLINICALTRIALS:gov: NCT04126577.

BACKGROUND:During atherogenesis, macrophages turn into foam cells by engulfing lipids present within the atheroma plaques. The shift of foam cells toward proinflammatory or anti-inflammatory phenotypes, a critical step in disease progression, is still poorly understood. LXRs (liver X receptors) play a pivotal role in the macrophage response to lipid, promoting the expression of key genes of cholesterol efflux, mitigating intracellular cholesterol accumulation. LXRs also exert balanced actions on inflammation in human macrophages, displaying both proinflammatory and anti-inflammatory effects. METHODS:Our study explored the role of LXRs in the functional response of human macrophage to lipid-rich plaque environment. We used primary human macrophages treated with atheroma plaque extracts and assessed the impact of pharmacological LXR inhibition by GSK2033 on cholesterol homeostasis and inflammatory response. Ultimately, we evaluated macrophage and endothelial cell cross talk by assessing the impact of macrophage-conditioned supernatants on the human endothelial cell. RESULTS:LXR inhibition by GSK2033 resulted in increased levels of cholesterol and oxysterols in human macrophages, alongside notable changes in the cholesterol ester profile. This was accompanied by heightened secretion of proinflammatory cytokines such as IL (interleukin)-6 and TNFα (tumor necrosis factor-α), despite a transcriptional repression of IL-1β. Conditioned media from GSK2033-treated macrophages more effectively activated ICAM-1 (intercellular adhesion molecule-1) and CCL2 (C-C motif ligand 2) expression in endothelial cells. CONCLUSIONS:Our findings illustrate the intricate relationship between LXR function, cholesterol metabolism, and inflammation in human macrophages. While LXR is required for the proper handling of plaque lipids by macrophages, the differential regulation of IL-1β versus IL-6/TNFα secretion by LXRs could be challenging for potential pharmacological interventions.

We aimed to evaluate the prognostic value of octanoyl-carnitine in patients undergoing surgical myocardial revascularization for coronary artery disease. We conducted a retrospective analysis of an existing prospective cohort aimed at studying risk factors for vasoplegia in patients undergoing cardiac surgery with cardiopulmonary bypass. We conducted our study exclusively on patients included in the prospective cohort at Dijon University Hospital in 2021. We included 42 adult patients undergoing coronary artery bypass grafting, either alone or combined with another surgical procedure. We collected plasma samples for each patient from EDTA-anticoagulated tubes, taken as part of routine biological check-ups according to the department protocol, at three time points: preoperatively, immediately postoperatively in the intensive care unit, and on the first postoperative day. Liquid chromatography coupled with tandem mass spectrometry was used to determine plasma levels of acyl-carnitines, including octanoyl-carnitine. The primary endpoint was the occurrence of major postoperative complications (stroke, atrial fibrillation, acute kidney injury, and/or death). Fourteen patients (33%) had major postoperative complications. Octanoyl-carnitine plasma concentration significantly increased during the perioperative period and was significantly associated with major postoperative complications at all three time points in coronary artery bypass grafting patients (T1: 14.2 [11.6; 18.6] vs 21.1 [14.8; 28.0], T2: 20.9 [16.4;27.9] vs 34.8 [21.2;37.2], T3: 22.8 [13.7;30.9] vs 34.4 [30.2;41.2]; p < 0.05; in nmol/l). At baseline, octanoyl-carnitine levels were higher in patients with complications, while other acyl-carnitines showed no significant differences. Octanoyl-carnitine is associated with mitochondrial metabolism and could be evaluated alone or in conjunction with clinical scores.

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their functions are in part dictated by their origin. We previously observed robust monocyte recruitment and contribution to the macrophage pool in brown adipose tissue. In particular, monocytes were predicted to give rise to two phenotypically distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. We found that bone marrow monocytes highly contributed to the CD226 + macrophage population while the CD206 + population contained mainly yolk sac-derived cells. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226 + macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226 + macrophages. Using meta-analysis of single cell RNA-sequencing data, we found that MDP-derived CD226 + macrophages were present in several tissues including peritoneal cavity, adrenal glands and all adipose depots, with a particular enrichment in beige and brown fat. A similar macrophage subset was identified in humans. Functionally, while depletion of CD206 + macrophages using anti-CD115 blocking antibodies led to decreased adipose triglyceride content, genetic depletion of CD226 + macrophages caused the opposite phenotype. We thus identify CD226 + MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.

BackgroundPerioperative inflammation is a predictor of surgical complications and cancer prognosis in surgical oncology. Multimodal protocols are ongoing in order to find ways to control inflammation. A preoperative flash high-dose of corticosteroids has been suggested as a way to control perioperative inflammation, but its safety in colorectal surgery needs to be established prior to a phase 3 trial. The physiologic effects of such a dose should also be explored.MethodsProspective bicentric phase 2 single-arm study with a biological ancillary study. Patients were administered 20 mg/kg of methyl-prednisone before colorectal surgery. Primary outcome was major post-operative complications defined as a grade >II according to the Dindo-Clavien classification. Ancillary outcome was plasma endotoxin concentration and activity.ResultsSixty-seven patients were included. Twelve (17.9 % [90 %CI:10.9 %-29.6 %]) patients developed major post-operative complications. No homeostatic disturbances troubles were observed. Severe postoperative hyperglycemia concerned 3 (4 %) patients which were all non-diabetic. The concentrations of endotoxin (mass) and its activity lowered between the pre-operative time point and the day after surgery.ConclusionPre-operative single flash of high dose methylprednisolone (20 mg/kg) before elective colorectal surgery seemed safe. Our results suggest that corticosteroids could promote gut barrier integrity, reducing endotoxemia in patients with colorectal surgery. Further studies (in particular a large randomized controlled trial) are needed to confirm our findings and explore a potential benefit of corticosteroid in this population.ClinicalTrials.gov03437746