New translational and experimental insights into the role of proresolving lipid mediators in inflammatory bowel disease

The resolution of inflammation is an active process,guided by specialized proresolution lipid mediators(SPMs).These mediators originate from polyunsaturated fatty acids,such as omega-3.Sufficient evidence suggests that the beneficial effects attributed to omega-3 are,at least in part,the result of the immunomodulatory action of the SPMs,which act systemically by overcoming inflammation and repairing tissue damage,without suppressing the immune response.Recent studies suggest that an imbalance in the synthesis and/or activity of these compounds may be associated with the pathogenesis of several inflammatory conditions,such as inflammatory bowel disease(IBD).Thus,this review highlights the advances made in recent years with regard to the endogenous synthesis and the biological role of lipoxins,resolvins,protectins,and maresins,as well as their precursors,in the regulation of inflammation;and provides an update on the participation of these mediators in the development and evolution of IBD and the therapeutic approaches that these immunomodulating substances are involved in this context.

Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

Plasma apo CⅢ Levels in Relation to Inflammatory Traits and Metabolic Syndrome in Patients not Treated with Lipid-lowering Drugs Undergoing Coronary Angiography

Objective Assessment of the comprehensive relationship among apolipoprotein CIII（apoCⅢ） levels, inflammation, and metabolic disorders is rare. Methods A total of 1455 consecutive patients not treated with lipid-lowering drugs and undergoing coronary angiography were enrolled in this cross-sectional study. A mediation analysis was used to detect the underlying role of apoCⅢ in the association of inflammation with metabolic syndrome（MetS）. Results Patients with MetS showed higher levels of apoCⅢ [95.1（73.1-131.4） vs. 81.7（58.6-112.4） μg/mL, P 〈 0.001] and inflammatory markers [high sensitivity C-reactive protein, 1.7（0.8-3.4） vs. 1.1（0.5-2.2） mg/L; white blood cell count,（6.48 ± 1.68） vs.（6.11 ± 1.67） × 10~9/L]. The levels of apoCⅢ and inflammatory markers increased with the number of metabolic risk components（all P 〈 0.001）. Furthermore, apoCⅢ levels were associated with virtually all individual MetS risk factors and inflammatory markers（all P 〈 0.05）. Importantly, the prevalence of MetS in each metabolic disorder rose as apoCⅢ levels increased（all P 〈 0.05）. Mediation analysis showed that apoCⅢ partially mediated the effect of inflammation on MetS independently from triglycerides. Conclusion Plasma apoCⅢ levels were significantly associated with the development and severity of MetS, and a role of apoCⅢ in the effect of inflammation on the development of MetS was identified.

The prevention of oxidative stress improve asthmatic inflammation

Asthma is a disease characterized by airway chronic inflammation and bronchial hyperactivity, involving the imbalance of oxidative and antioxidative agents. There is an increased free radical generation and a decreased antioxidant enzyme activity, which correlate with the severity of the disease. The oxidative stress triggers specific physiopathological changes in the respiratory tract as a result of proinflammatory molecule formation, such as isoprostanes and PAF- like lipids. The synthesis of these mediators is dependent on the availability of lipid substrates, such as PUFAs, which are present in cell membranes. Therefore, lipid oxidation may have an important role in the perpetuation and amplification of the asthmatic inflammatory response. This article will make considerations about how oxidative stress contributes to asthma pathogenesis.

Dietary arachidonate in milk replacer triggers dual benefits of PGE2 signaling in LPS-challenged piglet alveolar macrophages

Background: Respiratory infections challenge the swine industry, despite common medicinal practices. The dual signaling nature of PGE2(supporting both inflammation and resolution) makes it a potent regulator of immune cell function. Therefore, the use of dietary long chain n-6 PUFA to enhance PGE2 effects merits investigation.Methods: Day-old pigs(n = 60) were allotted to one of three dietary groups for 21 d(n = 20/diet), and received either a control diet(CON, arachidonate = 0.5% of total fatty acids), an arachidonate(ARA)-enriched diet(LC n-6,ARA = 2.2%), or an eicosapentaenoic(EPA)-enriched diet(LC n-3, EPA = 3.0%). Alveolar macrophages and lung parenchymal tissue were collected for fatty acid analysis. Isolated alveolar macrophages were stimulated with LPS in situ for 24 h, and m RNA was isolated to assess markers associated with inflammation and eicosanoid production.Culture media were collected to assess PGE2 secretion. Oxidative burst in macrophages was measured by: 1)oxygen consumption and extracellular acidification(via Seahorse), 2) cytoplasmic oxidation and 3) nitric oxide production following 4, 18, and 24 h of LPS stimulation.Results: Concentration of ARA(% of fatty acids, w/w) in macrophages from pigs fed LC n-6 was 86% higher than CON and 18% lower in pigs fed LC n-3(P < 0.01). Following LPS stimulation, abundance of COX-2 and TNF-α mRNA(P < 0.0001), and PGE2 secretion(P < 0. 01) were higher in LC n-6 PAM vs. CON. However, ALOX5 abundance was1.6-fold lower than CON. Macrophages from CON and LC n-6 groups were 4-fold higher in ALOX12/15 abundance(P < 0.0001) compared to LC n-3. Oxygen consumption and extracellular acidification rates increased over 4 h following LPS stimulation(P < 0.05) regardless of treatment. Similarly, increases in cytoplasmic oxidation(P < 0.001)and nitric oxide production(P < 0.002) were observed after 18 h of LPS stimulation but were unaffected by diet.Conclusions: We infer that enriching diets with arachidonic acid may be an effective means to enhance a stronger innate immunologic response to respiratory challenges in neonatal pigs. However, further work is needed to examine long-term safety, clinical efficacy and economic viability.

Molecular basis for the effect of lipid lowering drugs on growth factors after de-endothelialization

Objective To study the mechanism and effect of lipid lowering drugs in arresting the development of arterial restenosis after angioplasty. Methods De-endothelialization injury of rabbit aortae, common iliac and femoral arteries using balloon angioplasty and the expression of growth factors such as platelet derived growth factor-B (PDGF-B), transforming growth factor β-1 (TGFβ-1), and fibroblast growth factos (bFGF) were investigated. Total serum cholesterol (TC) and triglycerides (TG) were analyzed during and after the treatment using either simvastatin combined with gemfibrozil or simvastatin alone for 6 weeks.Results Serum total cholesterol and triglycerides were only slightly to moderately increased after high cholesterol ration intake lasting for 6 weeks in rabbits of two therapeutic groups (simvastatin plus gemfibrozil or only simvastatin). A positive correlation was found between TC and intimal/medial ratio (r=0.5873, P<0.05). PDGF-B detected by immuno-histochemistry and RT-PCR analysis showed that the release of PDGF-B was inhibited by simvastatin and gemfibrozil after de-endothelialization. RT-PCR analysis showed that TGFβ-1 was increased in the neointima in two treatment groups but no definite change was seen in the mRNA of bFGF in the smooth muscle cell (SMC) of the balloon-injured arteries even under lipid lowering drug treatment. Conclusion In addition to the lipid lowering effect, both simvastatin and gemfibrozil also influence the release of PDGF-Band TGF-1 in the neointima after de-endothelialization.

From Vietnamese plants to a biflavonoid that relieves inflammation by triggering the lipid mediator class switch to resolution

Chronic inflammation results from excessive pro-inflammatory signaling and the failure to resolve the inflammatory reaction.Lipid mediators orchestrate both the initiation and resolution of inflammation.Switching from pro-inflammatory to pro-resolving lipid mediator biosynthesis is considered as efficient strategy to relieve chronic inflammation,though drug candidates exhibiting such features are unknown.Starting from a library of Vietnamese medical plant extracts,we identified isomers of the biflavanoid 8-methylsocotrin-4’-ol from Dracaena cambodiana,which limit inflammation by targeting 5-lipoxygenase and switching the lipid mediator profile from leukotrienes to specialized pro-resolving mediators(SPM).Elucidation of the absolute configurations of 8-methylsocotrin-4’-ol revealed the 2 S,γSisomer being most active,and molecular docking studies suggest that the compound binds to an allosteric site between the 5-lipoxygenase subdomains.We identified additional subordinate targets within lipid mediator biosynthesis,including microsomal prostaglandin E2 synthase-1.Leukotriene production is efficiently suppressed in activated human neutrophils,macrophages,and blood,while the induction of SPM biosynthesis is restricted to M2 macrophages.The shift from leukotrienes to SPM was also evident in mouse peritonitis in vivo and accompanied by a substantial decrease in immune cell infiltration.In summary,we disclose a promising drug candidate that combines potent 5-lipoxygenase inhibition with the favorable reprogramming of lipid mediator profiles.

Expression of leukotriene B4 receptor 1 defines functionally distinct DCs that control allergic skin inflammation

Leukotriene B4(LTB4)receptor 1(BLT1)is a chemotactic G protein-coupled receptor expressed by leukocytes,such as granulocytes,macrophages,and activated T cells.Although there is growing evidence that BLT1 plays crucial roles in immune responses,its role in dendritic cells remains largely unknown.Here,we identified novel DC subsets defined by the expression of BLT1,namely,BLT1hi and BLT1lo DCs.We also found that BLT1hi and BLT1lo DCs differentially migrated toward LTB4 and CCL21,a lymph node-homing chemoattractant,respectively.By generating LTB4-producing enzyme LTA4H knockout mice and CD11c promoter-driven Cre recombinase-expressing BLT1 conditional knockout(BLT1 cKO)mice,we showed that the migration of BLT1hi DCs exacerbated allergic contact dermatitis.Comprehensive transcriptome analysis revealed that BLT1hi DCs preferentially induced Th1 differentiation by upregulating IL-12p35 expression,whereas BLT1lo DCs accelerated T cell proliferation by producing IL-2.Collectively,the data reveal an unexpected role for BLT1 as a novel DC subset marker and provide novel insights into the role of the LTB4-BLT1 axis in the spatiotemporal regulation of distinct DC subsets.

Limited potential of resolvin D1 in treatment of cholestatic liver fibrosis

Background:Several studies suggest a role for EPA-and DHA-derived pro-resolving mediators like resolvins in reversing metabolic and inflammatory disturbances seen in various chronic diseases.Here,we investigated the effects of resolvin D1(RvD1)on bile duct ligation(BDL)-induced cholestatic liver injury.Methods:Mice were treated daily with RvD1 or 0.1%ethanol(control)from the day of BDL until the final observation time points.Blood and liver tissue were collected 2,5 and 14 days after BDL for different analyses.Results:RvD1 treatment of mice had no impact on the extent of cholestatic liver injury upon BDL,neither in the acute phase nor in the progressive state of liver fibrosis.Although RvD1 treatment resulted in a significantly reduced activity of hepatic stellate cells as well as reduced deposition of extracellular matrix 2 days after BDL,mice were not protected from inflammation and further fibrosis progression.Conclusions:These data indicate that RvD1 has a limited therapeutic potential to treat cholestatic liver diseases,as it has no significant impact on regression of hepatic necroinflammation and fibrotic changes in bile duct-ligated mice.