Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

Chronic kidney disease pathogenesis involves both tubular and vascular injuries. Despite abundant investigations to identify the risk factors, the involvement of chronic endothelial dysfunction in developing nephropathies is insufficiently explored. Previously, soluble thrombomodulin (sTM), a cofactor in the activation of protein C, has been shown to protect endothelial function in models of acute kidney injury. In this study, the role for sTM in treating chronic kidney disease was explored by employing a mouse model of chronic vascular activation using endothelial-specific TNF-α-expressing (tie2-TNF) mice. Analysis of kidneys from these mice after 3 mo showed no apparent phenotype, whereas 6-mo-old mice demonstrated infiltration of CD45-positive leukocytes accompanied by upregulated gene expression of inflammatory chemokines, markers of kidney injury, and albuminuria. Intervention with murine sTM with biweekly subcutaneous injections during this window of disease development between months 3 and 6 prevented the development of kidney pathology. To better understand the mechanisms of these findings, we determined whether sTM could also prevent chronic endothelial cell activation in vitro. Indeed, treatment with sTM normalized increased chemokines, adhesion molecule expression, and reduced transmigration of monocytes in continuously activated TNF-expressing endothelial cells. Our results suggest that vascular inflammation associated with vulnerable endothelium can contribute to loss in renal function as suggested by the tie2-TNF mice, a unique model for studying the role of vascular activation and inflammation in chronic kidney disease. Furthermore, the ability to restore the endothelial balance by exogenous administration of sTM via downregulation of specific adhesion molecules and chemokines suggests a potential for therapeutic intervention in kidney disease associated with chronic inflammation.

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Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy385 ◽

2018 ◽

Vol 34 (11) ◽

pp. 1853-1863 ◽

Cited By ~ 4

Author(s):

Ruifeng Wang ◽

Titi Chen ◽

Chengshi Wang ◽

Zhiqiang Zhang ◽

Xin Maggie Wang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

T Cells ◽

T Cell ◽

Kidney Disease ◽

T Cell Activation ◽

Cell Activation ◽

Kidney Injury ◽

Public Health Problem ◽

Global Public Health ◽

Flt3 Inhibitor

Abstract Background Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. Methods To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. Results Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103− DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. Conclusion Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.

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Huaier Extract Attenuates Acute Kidney Injury to Chronic Kidney Disease Transition by Inhibiting Endoplasmic Reticulum Stress and Apoptosis via miR-1271 Upregulation

BioMed Research International ◽

10.1155/2020/9029868 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Jing-Ying Zhao ◽

Yu-Bin Wu

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Endoplasmic Reticulum ◽

Kidney Disease ◽

Endoplasmic Reticulum Stress ◽

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury

Endoplasmic reticulum stress (ERS) is strongly associated with acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Huaier extract (HE) protects against kidney injury; albeit, the underlying mechanism is unknown. We hypothesized that HE reduces kidney injury by inhibiting ERS. In this study, using an AKI-CKD mouse model of ischemia-reperfusion injury (IRI), we evaluated the effect of HE on AKI-CKD transition. We also explored the underlying molecular mechanisms in this animal model and in the HK-2 human kidney cell line. The results showed that HE treatment improved the renal function, demonstrated by a significant decrease in serum creatinine levels after IRI. HE appreciably reduced the degree of kidney injury and fibrosis and restored the expression of the microRNA miR-1271 after IRI. Furthermore, HE reduced the expression of ERS markers glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and inhibited apoptosis in the IRI group. This in vivo effect was supported by in vitro results in which HE inhibited apoptosis and decreased the expression of CHOP and GRP78 induced by ERS. We demonstrated that CHOP is a target of miR-1271. In conclusion, HE reduces kidney injury, probably by inhibiting apoptosis and decreasing the expression of GRP78 and CHOP via miR-1271 upregulation.

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Abstract 17562: GPCR Gβγ Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure Mice

Circulation ◽

10.1161/circ.132.suppl_3.17562 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Fadia A Kamal ◽

Joshua G Travers ◽

Allison E Schafer ◽

Qing Ma ◽

Prasad Devarajan ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Dysfunction ◽

G Protein ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Direct Role

Background: Cardiorenal syndrome type 2 (CRS2), the development of chronic kidney disease (CKD) secondary to chronic heart failure (CHF), is clinically associated with increased incidence of organ failure and reduced survival. Heart and kidney damage in CRS2 is greatly caused by chronic stimulation of the adrenergic and endothelin receptors as a result of elevated neurohormonal signaling of the sympathetic nervous system (SNS) and its downstream endothelin (ET) system, respectively. These receptors belong to the superfamily of G protein-coupled receptors (GPCRs). While chronic GPCR stimulation and its associated upregulated interaction between the G-protein βγ subunit (Gβγ), the GPCR-kinase 2 (GRK2) and β-arrestin are known to be central to various cardiovascular diseases, their role in kidney diseases are by far unknown and beg investigation. Objective: CRS2 animal studies utilize combine ischemic cardiac injury and renal injury, which is of poor clinical relevance. Our study investigates: (1) the development of chronic kidney disease (CKD) in a model of non-ischemic CHF without inducing surgical kidney injury, aiming to establish a more clinically relevant CRS2 model. (2) The possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in the established CRS2 model. Methods and results: We utilized transverse aortic constriction (TAC) as a non-ischemic hypertrophic murine CHF model. Twelve weeks after TAC, mice developed CKD secondary to CHF suggesting a CRS2 model. This was associated with elevated renal GPCR-Gβγ signaling and ET system expression. Importantly, systemic pharmacologic Gβγ inhibition by gallein attenuated these renal pathological changes in parallel with alleviated CHF. A direct effect of gallein on the kidney was subsequently confirmed in a bilateral ischemia reperfusion acute kidney injury (AKI) mouse model where it attenuated renal dysfunction, tissue damage and ET system activation, indicating a direct role for GPCR-Gβγ signaling in AKI. Further, in vitro studies in mouse embryonic fibroblasts showed a key role for ET receptor-Gβγ signaling in fibroblast activation. Conclusion: Our data suggest TAC as a clinically relevant CRS2 model and GPCR-Gβγ inhibition as a novel therapeutic approach for CRS2 and AKI.

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IL-35 Suppresses Lipopolysaccharide-Induced Endothelial Cell Activation Through Downregulation of MAPK Signaling-Mediated Upregulation of Adhesion Molecule VCAM-1

Blood ◽

10.1182/blood.v120.21.3310.3310 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3310-3310

Author(s):

Xiaojin Sha ◽

Shu Meng ◽

Xinyuan Li ◽

Jahaira Lopez Pastrana ◽

Hong Wang ◽

...

Keyword(s):

Endothelial Cell ◽

Adhesion Molecule ◽

Cell Activation ◽

Conflicts Of Interest ◽

Vascular Inflammation ◽

Endothelial Activation ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Interleukin 12 ◽

Endothelial Cell Activation

Abstract Abstract 3310 Our previous reports showed that survival/apoptosis of CD4+CD25+Foxp3+ regulatory T cells (Tregs) modulates vascular inflammation even though the mode of Tregs inhibition was unknown. Interleukin-35 (IL-35), consisting of two subunits Epstein-Barr virus–induced gene 3 (EBI3) and p35, is a novel anti-inflammatory cytokine, which is a member of the interleukin-12 (IL-12) cytokine family. IL-35 is produced by Tregs. It has been shown that IL-35 suppresses chronic inflammatory diseases such as asthma and inflammatory bowel diseases. However, an important question of whether IL-35 can carry out Tregs suppression and inhibit endothelial cell (EC) activation in acute inflammation remained unknown. Here we found that IL-35 significantly inhibits lung neutrophil infiltration into the surrounding areas of bronchioles and alveolar space when induced by intraperitoneal injection of lipopolysaccharide (LPS) in wild type mice and EBI3-deficient mice. Furthermore, cremaster microvasculature study using intravital microscopy showed IL-35 significantly suppresses leukocyte adhesion to the vascular wall as well, suggesting IL-35 inhibition of endothelial activation. Mechanistically, IL-35 inhibited LPS-induced upregulation of adhesion molecules on human aortic endothelial cells, a marker of endothelial activation, including vascular cell adhesion molecule 1 (VCAM-1). IL-35 acted through new IL-35 dimeric receptors gp130 and IL-12Rβ2, and inhibited VCAM-1 promoter transcription in mitogen-activated protein kinase (MAPK)-mediated pathway. These results provide a novel insight on Tregs and IL-35 inhibition of vascular inflammation. Disclosures: No relevant conflicts of interest to declare.

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A novel flow cytometry-based quantitative monocyte adhesion assay to estimate endothelial cell activation in vitro

BioTechniques ◽

10.2144/btn-2019-0169 ◽

2020 ◽

Vol 68 (6) ◽

pp. 325-333

Author(s):

Vinnyfred Vincent ◽

Himani Thakkar ◽

Anjali Verma ◽

Atanu Sen ◽

Nikhil Chandran ◽

...

Keyword(s):

Flow Cytometry ◽

Endothelial Cells ◽

Endothelial Cell ◽

Cell Activation ◽

Endothelial Activation ◽

Adhesion Assay ◽

Monocyte Adhesion ◽

Endothelial Cell Activation ◽

Functional Level

One of the earliest events in the development of atherosclerosis is endothelial activation, which is estimated in vitro at the functional level by quantifying monocyte adhesion. This involves the incubation of fluorescently labeled monocytes on top of cultured endothelial cells and quantifying the number of adhered monocytes. Currently, the quantification of adhered monocytes is done using microscopy or by lysing the cells and estimating the fluorescence. Here we present a novel flow cytometry-based method for the quantification of monocyte adhesion. This method could quantify the average number of monocytes adhered to a single endothelial cell after monocyte adhesion assay, and was also sensitive to the level of activation of endothelial cells. Flow cytometry-based quantification requires less time and effort compared with microscopy-based quantification.

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432. How do antiphospholipid antibodies contribute to preeclampsia?

Reproduction Fertility and Development ◽

10.1071/srb08abs432 ◽

2008 ◽

Vol 20 (9) ◽

pp. 112

Author(s):

Q. Chen ◽

C. Viall ◽

P. R. Stone ◽

L. W. Chamley

Keyword(s):

Endothelial Cell ◽

Antiphospholipid Antibodies ◽

Cell Activation ◽

Fold Increase ◽

First Trimester ◽

Endothelial Activation ◽

Maternal Blood ◽

Endothelial Cell Activation

Preeclampsia is characterised by elevated maternal blood pressure which is preceded by endothelial activation. The cause of this endothelial cell dysfunction is unclear but it appears to be triggered by a placental factor. One of the risk factors for developing preeclampsia is the presence of antiphospholipid antibodies (aPL) in the maternal blood but exactly how aPL predispose women to developing preeclampsia is unclear. A second feature known to be associated with preeclampsia is excessive shedding and deportation of dead trophoblasts. We have previously shown that shed trophoblasts are phagocytosed by endothelial cells and that phagocytosis of necrotic trophoblasts leads to endothelial cell activation1. In this study we examined the hypothesis that aPL alter the number or nature of trophoblasts shed from the placenta resulting in endothelial cell activation. Using our published model of trophoblast shedding 2 human first trimester placental explants were treated with monoclonal aPL, IIC5 or ID2, or control antibody CD45 for 72 h. Shed trophoblasts then were harvested and counted using a Cellometer AutoT4 automated cell counter. The activity of caspases 3&7 was analysed in all treated shed trophoblasts using a FLICA™ kit. The treated shed trophoblasts also were exposed to the endothelial cell line HMEC-1 for 24 h. The level of ICAM-1 by HMEC-1 was determined by cell-based ELISA. The number of trophoblasts shed from placental explants was increased 2 fold following aPL treatment whereas, treatment with CD45 resulted in only a 1.3 fold increase in shedding. Trophoblasts shed from aPL-treated explants contained less active caspases 3 & 7 compared with control shed trophoblasts. Moreover, phagocytosis of trophoblasts shed from aPL-treated explants induced significantly increased expression of ICAM-1 compared with controls. aPL treatment affected the number and nature of trophoblasts shed from placentae in such a way that phagocytosing endothelium become activated. These findings suggest that aPL treatment may have shifted the type of cell death that shed trophoblasts are undergoing from apoptosis to a more necrotic or aponecrotic mechanism. This type of shedding of trophoblasts in vivo might contribute to the endothelial cell activation which is a hallmark feature of preeclampsia. (1) Chen Q, Stone PR, McCowan LM et al. Phagocytosis of necrotic but not apoptotic trophoblasts induces endothelial cell activation. Hypertension. 2006;47:116–121. (2) Abumaree MH, Stone PR, Chamley LW. An in vitro model of human placental trophoblast deportation/shedding. Mol Hum Reprod. 2006;12:687–694.

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Leucine-Rich α-2-Glycoprotein 1 Suppresses Endothelial Cell Activation Through ADAM10-Mediated Shedding of TNF-α Receptor

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.706143 ◽

2021 ◽

Vol 9 ◽

Author(s):

Kuin Tian Pang ◽

Mean Ghim ◽

Chenghao Liu ◽

Hui Min Tay ◽

Chee Wai Fhu ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Cell Activation ◽

Elevated Serum ◽

Endothelial Activation ◽

Endothelial Cell Activation ◽

Tnf Α ◽

Necrosis Factor

Elevated serum concentrations of leucine-rich α-2-glycoprotein (LRG1) have been reported in patients with inflammatory, autoimmune, and cardiovascular diseases. This study aims to investigate the role of LRG1 in endothelial activation. LRG1 in endothelial cells (ECs) of arteries and serum of patients with critical limb ischemia (CLI) was assessed by immunohistochemistry and ELISA, respectively. LRG1 expression in sheared and tumor necrosis factor-α (TNF-α)-treated ECs was analyzed. The mechanistic role of LRG1 in endothelial activation was studied in vitro. Plasma of 37-week-old Lrg1–/– mice was used to investigate causality between LRG1 and tumor necrosis factor receptor 1 (TNFR1) shedding. LRG1 was highly expressed in ECs of stenotic but not normal arteries. LRG1 concentrations in serum of patients with CLI were elevated compared to healthy controls. LRG1 expression was shear dependent. It could be induced by TNF-α, and the induction of its expression was mediated by NF-κB activation. LRG1 inhibited TNF-α-induced activation of NF-κB signaling, expression of VCAM-1 and ICAM-1, and monocyte capture, firm adhesion, and transendothelial migration. Mechanistically, LRG1 exerted its function by causing the shedding of TNFR1 via the ALK5-SMAD2 pathway and the subsequent activation of ADAM10. Consistent with this mechanism, LRG1 and sTNFR1 concentrations were correlated in the serum of CLI patients. Causality between LRG1 and TNFR1 shedding was established by showing that Lrg1–/–mice had lower plasma sTNFR1 concentrations than wild type mice. Our results demonstrate a novel role for LRG1 in endothelial activation and its potential therapeutic role in inflammatory diseases should be investigated further.

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Exogenous Wnt1 Prevents Acute Kidney Injury and Its Subsequent Progression to Chronic Kidney Disease

Frontiers in Physiology ◽

10.3389/fphys.2021.745816 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xue Hong ◽

Yanni Zhou ◽

Dedong Wang ◽

Fuping Lyu ◽

Tianjun Guan ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Blood Biochemical

Studies suggest that Wnt/β-catenin agonists are beneficial in the treatment of acute kidney injury (AKI); however, it remains elusive about its role in the prevention of AKI and its progression to chronic kidney disease (CKD). In this study, renal Wnt/β-catenin signaling was either activated by overexpression of exogenous Wnt1 or inhibited by administration with ICG-001, a small molecule inhibitor of β-catenin signaling, before mice were subjected to ischemia/reperfusion injury (IRI) to induce AKI and subsequent CKD. Our results showed that in vivo expression of exogenous Wnt1 before IR protected mice against AKI, and impeded the progression of AKI to CKD in mice, as evidenced by both blood biochemical and kidney histological analyses. In contrast, pre-treatment of ICG-001 before IR had no effect on renal Wnt/β-catenin signaling or the progression of AKI to CKD. Mechanistically, in vivo expression of exogenous Wnt1 before IR suppressed the expression of proapoptotic proteins in AKI mice, and reduced inflammatory responses in both AKI and CKD mice. Additionally, exogenous Wnt1 inhibited apoptosis of tubular cells induced by hypoxia-reoxygenation (H/R) treatment in vitro. To conclude, the present study provides evidences to support the preventive effect of Wnt/β-catenin activation on IR-related AKI and its subsequent progression to CKD.

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Potential to Target Circulating miRNAs, Indicative of Renal Fibrosis, in Canines with Chronic Kidney Disease Through Dietary Intervention

Current Developments in Nutrition ◽

10.1093/cdn/nzaa068_024 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1539-1539

Author(s):

Selena Tavener ◽

Kiran Panickar

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Dietary Intervention ◽

Kidney Injury ◽

Experimental Models ◽

Circulating Mirnas ◽

Down Regulation ◽

Renal Fibrogenesis

Abstract Objectives Mature microRNAs (miRNAs) are single-stranded RNAs approximately 22 nucleotides in length that act as posttranscriptional regulators by base-pairing with complementary sequences to mRNAs, leading to the silencing of mRNA. Circulating miRNAs may also serve as biomarkers for renal dysfunction including renal fibrosis which results in a progressive loss of renal function. We assessed circulating levels of miRNAs in the blood of dogs that were clinically diagnosed as having chronic kidney disease (CKD), post-mortem. Methods We used Qiagen's Canine mScript miRNA PCR array from blood samples that were collected at necropsy from dogs with CKD (n = 10; 2–17 yr) and control dogs (n = 10; 5–13.5 yr). End-of-life pathology reports indicated interstitial inflammation, fibrosis, and thickening of the Bowman's capsule. Results There was a significant decline in the levels of miRNAs cfa-let-7a, let-7c, let-7f, and let-7g in dogs with CKD when compared to controls (P < 0.05). Down-regulation of certain let-7 miRNAs (let-7a, let-7b) has been associated with experimental models of induction of renal fibrogenesis. There was also a > 2-fold reduction (ns) in levels of cfa-miR-93, cfa-miR-122, cfa-miR-200a, and cfa-miR-204, in CKD when compared to controls. These microRNAs have been demonstrated to have anti-fibrogenesis effect, and are also down-regulated in rodent models and in vitro mechanistic models of renal fibrosis leading to increased fibrosis. There was also a down-regulation of cfa-miR-16, which is consistent with its reported role in attenuating kidney injury independent of fibrosis. Taken together with the literature, down-regulation of these miRNAs may be indicative of a reduction in their role in attenuating renal fibrogenesis and injury. Importantly, the circulating miRNAs may serve as non-invasive biomarkers for renal fibrosis in CKD and also as nutritional targets for slowing the progression of fibrosis in kidney disease. Conclusions Our data show evidence of renal fibrosis markers that could have contributed to a progressive decline in kidney function. Nutritional therapy to slow the progression of kidney dysfunction may benefit from dietary ingredients including polyphenols that have been shown to upregulate miRNAs. Funding Sources Funded by Hills PNC, Inc.

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Abstract 159: Synthetic High Density Lipoprotein - a Potential Therapy for Sepsis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.159 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Ling Guo ◽

Emily E Morin ◽

Yaxia Yuan ◽

Chang-Guo Zhan ◽

Ming-Cui Gong ◽

...

Keyword(s):

Cell Activation ◽

Cecal Ligation ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Endothelial Activation ◽

Endothelial Cell Activation ◽

Protective Mechanisms ◽

Sepsis Therapy ◽

New Generation

Introduction: Sepsis is the leading cause of death in critically ill patients with mortality rates exceeding 30%. The ability of endogenous HDL to neutralize and facilitate elimination of lipopolysaccharides (LPS) is known and synthetic HDLs (sHDL) have been administered in sepsis models with varying success. In the current study we optimized composition of sHDL, apolipoprotein A-I (apoA-I) mimetic peptide-phospholipid particles, to maximize their protective effect against endothelial dysfunction in sepsis, and examined changes in HDL and apoA-I levels in patients with sepsis to select sHDL doses for evaluation in a sepsis animal model. Methods/Results: We first measured HDL cholesterol (HDL-C) and apoA-I in patients at time of intake to the intensive care unit, observing HDL to be 45% lower in septic patients compared to non-septic patients (p<0.01), with HDL levels in non-surviving septic patients being significantly lower compared to those in surviving septic patients (p<0.01). Next, we tested a new generation of sHDL, ETC642, for its efficacy on cecal ligation and puncture (CLP)-challenged mice. We administered sHDL to mice 2h post CLP and found that sHDL treatment significantly increased plasma HDL-C and decreased BUN, plasma IL-6 and IL-10 levels. More importantly, sHDL therapy improved 7d survival rate greater than 2-fold over PBS treated mice (p=0.01). To understand the mechanisms underlying sHDL protection, we investigated the effect of sHDL on endotoxin-induced inflammatory response in vitro . sHDL not only neutralized LPS/LTA but also suppressed TLR4-/TLR2-NF-kB signaling in macrophages, and inhibited LPS/LTA/TNF-α induced endothelial cell activation. Conclusions: In this study, we show that HDL-C levels are markedly decreased in septic patients, which is associated with poor prognosis. We demonstrate that sHDL treatment increases HDL levels and effectively protects against CLP-induced septic death. We further established that sHDL therapy provides multiple protective mechanisms through LPS/LTA detoxification, suppressing inflammatory signaling in macrophages and inhibiting endothelial activation. Together, our findings suggest that targeting the vasculature via sHDL can be an effective platform for sepsis therapy.

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