Lipoxins: resolutionary road Maderna, Paola; Godson, Catherine
British journal of pharmacology,
October 2009, Volume:
158, Issue:
4
Journal Article
Peer reviewed
Open access
The resolution of inflammation is an active process controlled by endogenous mediators with selective actions on neutrophils and monocytes. The initial phase of the acute inflammatory response is ...characterized by the production of pro‐inflammatory mediators followed by a second phase in which lipid mediators with pro‐resolution activities may be generated. The identification of these mediators has provided evidence for the dynamic regulation of the resolution of inflammation. Among these endogenous local mediators of resolution, lipoxins (LXs), lipid mediators typically formed during cell–cell interaction, were the first to be recognized. More recently, families of endogenous chemical mediators, termed resolvins and protectins, were discovered. LXs and aspirin‐triggered LXs are considered to act as ‘braking signals’ in inflammation, limiting the trafficking of leukocytes to the inflammatory site. LXs are actively involved in the resolution of inflammation stimulating non‐phlogistic phagocytosis of apoptotic cells by macrophages. Furthermore, LXs have emerged as potential anti‐fibrotic mediators that may influence pro‐fibrotic cytokines and matrix‐associated gene expression in response to growth factors. Here, we provide a review and an update of the biosynthesis, metabolism and bioactions of LXs and LX analogues, and the recent studies on their therapeutic potential as promoters of resolution and fibro‐suppressants.
This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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•Inflammatory molecules play a central role in the pathogenesis of DKD.•Inflammation initiation and resolution is a highly regulated host response.•Specialized pro-resolving lipid ...mediators (SPMs) promote the resolution of inflammation.•SPMs are being investigated to treat chronic inflammation in DKD.
Renal microvascular disease associated with diabetes Diabetic kidney disease - DKD is the leading cause of chronic kidney disease. In DKD, glomerular basement membrane thickening, mesangial expansion, endothelial dysfunction, podocyte cell loss and renal tubule injury contribute to progressive glomerulosclerosis and tubulointerstitial fibrosis. Chronic inflammation is recognized as a major pathogenic mechanism for DKD, with resident and circulating immune cells interacting with local kidney cell populations to provoke an inflammatory response. The onset of inflammation is driven by the release of well described proinflammatory mediators, and this is typically followed by a resolution phase. Inflammation resolution is achieved through the bioactions of endogenous specialized pro-resolving lipid mediators (SPMs). As our understanding of SPMs advances ‘resolution pharmacology’ based approaches using these molecules are being explored in DKD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic ...acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c+ M1-macrophages (MΦs), while restoring CD206+ M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin−/− mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies.
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•Lipoxins attenuated high-fat diet-induced liver and kidney disease•LXA4 attenuated adipose inflammation, promoting a macrophage M1-to-M2 switch•LXA4 restored obesity-induced attenuation of autophagy markers LC3-II and p62•LXA4-mediated protection was adiponectin independent, but restored Annexin-A1
Börgeson et al. investigated the role of anti-inflammatory lipid mediators in obesity. LipoxinA4 and a synthetic lipoxin analog protected against obesity-induced kidney and liver disease. Lipoxins mediated protection by decreasing adipose inflammation and promoting a macrophage M1-to-M2 switch. Lipoxin-mediated protection was adiponectin independent, but correlated with restored adipose Annexin-A1 levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A mouse model of airway contraction in asthma, together with analyses of the human lung, indicates that maresin conjugates, a family of lipid mediators, play a role in the resolution of inflammation. ...Might these lipids represent a pharmacologic target in the treatment of inflammatory disorders?
Macrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory ...responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response.
Human THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE
) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE
mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 μg/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for MΦ1 and MΦ2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE
mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry.
Liraglutide decreased atherosclerotic lesion formation in ApoE
mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in MΦ0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the MΦ2 surface marker mannose receptor in both MΦ0 and MΦ2 macrophages. Significant reduction in total lesion development was found with once daily 300 μg/kg liraglutide treatment in ApoE
mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated MΦ1 markers (CCR7, IL-6 and TNF-alpha), augmented MΦ2 cell markers (Arg-1, IL-10 and CD163) and finally decreased MΦ1-like monocytes and macrophages from bone marrow-derived cells.
This data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards MΦ2 pro-resolving macrophages.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
One way to develop innovative approaches for the treatment of chronic diseases is to exploit the biology of the resolution of inflammation. With this terminology, we identify the integrated and ...complex network of mediators and pathways that ensure a timely and spatially regulated inflammatory response. Pro‐resolving mediators act on specific receptors. This provides an opportunity for developing a new arm of pharmacology we have termed “resolution pharmacology.” Here we present the reasoning behind the need to develop new medicines based on resolution and use a prototype GPCR as an example. Understanding how the formyl peptide receptor type 2 (FPR2) operates in a cell‐specific manner can guide the development of agonists as new therapeutics that could be of benefit as a therapy or co‐therapy for several diseases that affect our society. FPR2 agonists would be among the first drugs to establish “resolution pharmacology” as the pharmacological approach for the third decade of the millennium.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Hypoxia is a feature of the microenvironment of a growing tumor. The transcription factor NFκB is activated in hypoxia, an event that has significant implications for tumor progression. Here, we ...demonstrate that hypoxia activates NFκB through a pathway involving activation of IκB kinase-β (IKKβ) leading to phosphorylation-dependent degradation of IκBα and liberation of NFκB. Furthermore, through increasing the pool and/or activation potential of IKKβ, hypoxia amplifies cellular sensitivity to stimulation with TNFα. Within its activation loop, IKKβ contains an evolutionarily conserved LxxLAP consensus motif for hydroxylation by prolyl hydroxylases (PHDs). Mimicking hypoxia by treatment of cells with siRNA against PHD-1 or PHD-2 or the pan-prolyl hydroxylase inhibitor DMOG results in NFκB activation. Conversely, overexpression of PHD-1 decreases cytokine-stimulated NFκB reporter activity, further suggesting a repressive role for PHD-1 in controlling the activity of NFκB. Hypoxia increases both the expression and activity of IKKβ, and site-directed mutagenesis of the proline residue (P191A) of the putative IKKβ hydroxylation site results in a loss of hypoxic inducibility. Thus, we hypothesize that hypoxia releases repression of NFκB activity through decreased PHD-dependent hydroxylation of IKKβ, an event that may contribute to tumor development and progression through amplification of tumorigenic signaling pathways. IKK
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Hypoxia-sensitive pathways in inflammation-driven fibrosis Manresa, Mario C; Godson, Catherine; Taylor, Cormac T
American journal of physiology. Regulatory, integrative and comparative physiology,
2014-Dec-15, 2014-12-15, 20141215, Volume:
307, Issue:
12
Journal Article
Peer reviewed
Tissue injury can occur for a variety of reasons, including physical damage, infection, and ischemia. The ability of tissues to effectively recover from injury is a cornerstone of human health. The ...healing response in tissues is conserved across organs and typically involves distinct but overlapping inflammatory, proliferative, and maturation/resolution phases. If the inflammatory phase is not successfully controlled and appropriately resolved, an excessive healing response characterized by scar formation can lead to tissue fibrosis, a major clinical complication in disorders such as Crohn's disease (CD). As a result of enhanced metabolic and inflammatory processes during chronic inflammation, profound changes in tissue oxygen levels occur leading to localized tissue hypoxia. Therefore, inflammation, fibrosis, and hypoxia are coincidental events during inflammation-driven fibrosis. Our current understanding of the mechanism(s) underpinning fibrosis is limited as are the therapeutic options available. In this review, we discuss what is known about the cellular and molecular mechanisms underpinning inflammation-driven fibrosis and how hypoxia may play a role in shaping this process.
Clearance of apoptotic cells by phagocytic cells plays a significant role in the resolution of inflammation, protecting tissue from harmful exposure to the inflammatory and immunogenic contents of ...dying cells. Apoptosis induces cell surface changes that are important for recognition and engulfment of cells by phagocytes. These changes include alterations in surface sugars, externalization of phosphatidylserine and qualitative changes in the adhesion molecule ICAM-3. Several studies have contributed to clarify the role of the receptors on the surface of phagocytes that are involved in apoptotic cell clearance. The phagocytic removal of apoptotic cells does not elicit pro-inflammatory responses; in contrast, apoptotic cell engulfment appears to activate signals that suppress release of pro-inflammatory cytokines. Therefore, clearance of apoptotic leucocytes is implicated in the resolution of inflammation and mounting evidence suggests that defective clearance of apoptotic cells contributes to inflammatory and autoimmune diseases. Defining the ligands on apoptotic cells and the corresponding receptors on phagocytes with which they engage, is likely to lead to the development of novel anti-inflammatory pro-resolution drugs. In this article, we will review the recognition and signaling mechanisms involved in the phagocytosis of apoptotic cells as well as the role of endogenous compounds that play a relevant role in the modulation of inflammation. We will also discuss what is currently known about diseases that may reflect impaired phagocytosis and the consequences on inflammation and immune responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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