Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

Background: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).

Methods: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers () and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes).

CCR2 deficiency alters activation of microglia subsets in traumatic brain injury.

In traumatic brain injury (TBI), a diversity of brain resident and peripherally derived myeloid cells have the potential to worsen damage and/or to assist in healing. We define the heterogeneity of microglia and macrophage phenotypes during TBI in wild-type (WT) mice and Ccr2 mice, which lack macrophage influx following TBI and are resistant to brain damage. We use unbiased single-cell RNA sequencing methods to uncover 25 microglia, monocyte/macrophage, and dendritic cell subsets in acute TBI and normal brains.

Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV.

Background: Novel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear.

Methods: We assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS).

Urine Biomarkers of Kidney Tubule Health and Incident CKD Stage 3 in Women Living With HIV: A Repeated Measures Study.

Rationale & Objective: Single measurements of urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in HIV infection, but the prognostic value of repeat measurements over time is unknown.

Study Design: Cohort study.

Setting & Participants: 647 women living with HIV infection enrolled in the Women's Interagency Health Study.

Kidney tubule health scores and their associations with incident CKD in women living with HIV.

Objectives: Individual kidney tubule biomarkers are associated with chronic kidney disease (CKD) risk in people living with HIV (PLWH). Whether a combination of kidney biomarkers can be integrated into informative summary scores for PLWH is unknown.

Methods: We measured eight urine biomarkers of kidney tubule health at two visits over a 3-year period in 647 women living with HIV in the Women's Interagency Health Study.

HIV preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and changes in kidney function and tubular health.

Objective: To evaluate the effects of HIV preexposure prophylaxis (PrEP) with tenofovir disoproxial fumurate (TDF)/emtricitabine (FTC) on kidney function and kidney tubular health.

Design: The Iniciativa Profilaxis Pre-Exposicion open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. This study included 123 iPrEx-OLE participants who demonstrated PrEP adherence.

Altered overnight levels of pro-inflammatory cytokines in men and women with posttraumatic stress disorder.

Background: Posttraumatic stress disorder (PTSD) is associated with disturbed sleep and elevated levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Studies in animals and healthy humans have also shown that disrupted sleep elevates pro-inflammatory cytokines, including IL-6 and TNF-α. A better understanding of overnight cytokine levels and sleep might shed light on possible mechanisms for elevated inflammation in PTSD.

Altered inflammatory activity associated with reduced hippocampal volume and more severe posttraumatic stress symptoms in Gulf War veterans.

Background: Inflammation may reduce hippocampal volume by blocking neurogenesis and promoting neurodegeneration. Posttraumatic stress disorder (PTSD) has been linked with both elevated inflammation and reduced hippocampal volume. However, few studies have examined associations between inflammatory markers and hippocampal volume, and none have examined these associations in the context of PTSD.

Depletion of B-cells with rituximab improves endothelial function and reduces inflammation among individuals with rheumatoid arthritis.

Background: Individuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B-cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B-cells, is an effective therapy for RA.

Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages.

Many of the beneficial and adverse effects of niacin are mediated via a G protein receptor, G protein-coupled receptor 109A/hydroxycarboxylic acid 2 receptor (GPR109A/HCA2), which is highly expressed in adipose tissue and macrophages. Here we demonstrate that immune activation increases GPR109A/HCA2 expression. Lipopolysaccharide (LPS), TNF, and interleukin (IL) 1 increase GPR109A/HCA2 expression 3- to 5-fold in adipose tissue.

Mechanisms of triglyceride accumulation in activated macrophages.

LPS treatment of macrophages induces TG accumulation, which is accentuated by TG-rich lipoproteins or FFA. We defined pathways altered during macrophage activation that contribute to TG accumulation. Glucose uptake increased with activation, accompanied by increased GLUT1.

Angiopoietin like protein 4 expression is decreased in activated macrophages.

Angiopoietin like protein 4 (ANGPTL4) inhibits lipoprotein lipase (LPL) activity. Previous studies have shown that Toll-like Receptor (TLR) activation increases serum levels of ANGPTL4 and expression of ANGPTL4 in liver, heart, muscle, and adipose tissue in mice. ANGPTL4 is expressed in macrophages and is induced by inflammatory saturated fatty acids.

FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis.

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold.

Inflammation inhibits GPR81 expression in adipose tissue.

Objective And Design: The aim of this study was to examine the expression of G protein-coupled receptor 81 (GPR81) in mouse adipose tissue in response to inflammatory stimuli. GPR81 is activated by lactate resulting in the inhibition of lipolysis.

Materials And Treatment: Mice were injected with saline, lipopolysaccharide (LPS), zymosan, or turpentine, N = 5 per group.

Inflammation inhibits the expression of phosphoenolpyruvate carboxykinase in liver and adipose tissue.

Inhibition of adipocyte triglyceride biosynthesis is required for fatty acid mobilization during inflammation. Triglyceride biosynthesis requires glycerol 3-phosphate and phosphoenolpyruvate carboxykinase (PEPCK) plays a key role. We demonstrate that LPS, zymosan, and TNF-α decrease PEPCK in liver and fat.

Levels of plasma fibrinogen are elevated in well-controlled rheumatoid arthritis.

Objective: Patients with RA have systemic inflammation and increased risk of cardiovascular (CV) events, including thrombosis. Levels of fibrinogen, a pro-thrombotic protein with predictive value for CV disease (CVD), are elevated during systemic inflammation. We compared circulating fibrinogen levels in patients with RA with healthy controls and evaluated the relationship with measures of disease activity.

Endotoxin, zymosan, and cytokines decrease the expression of the transcription factor, carbohydrate response element binding protein, and its target genes.

Carbohydrate response element binding protein (ChREBP) is a recently discovered transcription factor whose levels and activity are increased by glucose leading to the activation of target genes, which include acetyl-CoA carboxylase, fatty acid synthase, and liver-type pyruvate kinase. Here, we demonstrate that lipopolysaccharide (LPS) treatment causes a marked decrease in ChREBP mRNA and protein levels in the liver of mice fed a normal chow diet or in mice fasted for 24 h and then re-fed a high carbohydrate diet. This decrease occurs rapidly and is a sensitive response (half-maximal dose 0.

The acute phase response stimulates the expression of angiopoietin like protein 4.

The acute phase response is characterized by elevations in serum triglyceride levels due to both an increase in hepatic VLDL production and a delay in the clearance of triglyceride rich lipoproteins secondary to a decrease in lipoprotein lipase (LPL) activity. Recently there has been a marked increase in our understanding of factors that regulate LPL activity. GPIHBP1 facilitates the interaction of LPL and lipoproteins thereby allowing lipolysis to occur.

ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists.

Activation of macrophages by TLR agonists enhances foam cell formation, but the underlying mechanisms are not understood. We examined the effects of TLR agonists on ADRP/ADFP, a protein associated with forming lipid droplets, and Mal1 a fatty acid-binding protein, in two mouse macrophage cell lines and human monocytes. Low doses of LPS, a TLR4 agonist increased both mRNA and protein levels of ADRP/ADFP and Mal1 in RAW 264.

Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm.

Respiratory failure is a major cause of mortality during septic shock and is due in part to decreased ventilatory muscle contraction. Ventilatory muscles have high energy demands; fatty acid (FA) oxidation is an important source of ATP. FA oxidation is regulated by nuclear hormone receptors; studies have shown that the expression of these receptors is decreased in liver, heart, and kidney during sepsis.

LPS and proinflammatory cytokines decrease lipin-1 in mouse adipose tissue and 3T3-L1 adipocytes.

Infection and inflammation affect adipose triglyceride metabolism, resulting in increased plasma free fatty acid (FFA) and VLDL levels during the acute-phase response. Lipin-1, a multifunctional protein, plays a critical role in adipose differentiation, mitochondrial oxidation, and triglyceride synthesis. Here, we examined whether LPS [a Toll-like receptor (TLR)-4 activator], zymosan (a TLR-2 activator), and proinflammatory cytokines regulate lipin-1 in adipose tissue.

Inflammation stimulates the expression of PCSK9.

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here, we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased.

LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney.

Inflammation produces marked changes in lipid metabolism, including increased serum fatty acids (FAs) and triglycerides (TGs), increased hepatic TG production and VLDL secretion, increased adipose tissue lipolysis, and decreased FA oxidation in liver and heart. Lipopolysaccharide (LPS) also increases TG and cholesteryl ester levels in kidneys. Here we confirm these findings and define potential mechanisms.

Infection and inflammation decrease apolipoprotein M expression.

Inflammation can produce abnormalities that could increase the risk for atherosclerosis including alterations in lipid and lipoprotein metabolism. Apolipoprotein M is a recently described HDL-associated apoprotein expressed mainly in the liver and kidney with protective effects against atherosclerosis. In this study, we describe the regulation of apolipoprotein M during the acute phase response.

Expression of the phospholipid scramblase (PLSCR) gene family during the acute phase response.

Phospholipid scramblase 1 (PLSCR1) is a member of PLSCR gene family that has been implicated in multiple cellular processes including movement of phospholipids, gene regulation, immuno-activation, and cell proliferation/apoptosis. In the present study, we identified PLSCR1 as a positive intracellular acute phase protein that is upregulated by LPS in liver, heart, and adipose tissue, but not skeletal muscle. LPS administration resulted in a marked increase in PLSCR1 mRNA and protein levels in the liver.