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The role of lipoxins in cardiometabolic physiology and disease

Börgeson, Emma

Cardiovascular Endocrinology & Metabolism: March 2016 - Volume 5 - Issue 1 - p 4–13
doi: 10.1097/XCE.0000000000000068
Reviews

Cardiometabolic pathophysiology is increasing in prevalence as a result of the escalating obesity pandemic. The search for novel therapeutics is ongoing and the strong interrelationship between diabetes and cardiovascular disease places emphasis on the need for drugs that target both pathologies, without interlinking side effects. Impaired inflammatory resolution may be the common denominator driving metabolic syndrome, diabetes, and cardiovascular disease. An interesting therapeutic approach would therefore be to promote the inflammatory resolution to subvert cardiometabolic disease. Inflammatory resolution is regulated by specialized proresolving lipid mediators: the ω3-polyunsaturated fatty acid-derived protectins, resolvins and maresins, and the ω6-polyunsaturated fatty acid-derived lipoxin (LX) A4 and LXB4. Here, we review novel evidence of how LXs may reduce pathological features associated with cardiometabolic disease. Recent evidence shows that LXs promote the resolution of obesity-induced adipose inflammation and systemic pathology. Furthermore, LXs attenuate cardinal processes associated with atherosclerotic plaque formation, for example, neutrophil recruitment, activation, and neutrophil extracellular traps formation, while promoting a proresolving MΦ phenotype and enhancing efferocytosis. Finally, LXs inhibit angiogenic pathways, including endothelial proliferation and activation, while reducing platelet-neutrophil aggregation. Collectively, LXs may have therapeutic potential in attenuating cardiometabolic pathophysiology.

Department of Medicine, Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Institute for Metabolomic Medicine, University of California San Diego, La Jolla, California, USA

Correspondence to Emma Börgeson, PhD, Department of Medicine, Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Institute for Metabolomic Medicine, University of California San Diego, La Jolla, CA 92093, USA Tel: +1 858 405 8293; fax: +1 858 822 7483; e-mail: kborgeson@ucsd.edu

Received August 25, 2015

Accepted September 15, 2015

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Introduction: cardiometabolic pathophysiology

Cardiometabolic disease is becoming a commonly used concept as we recognize the strong interrelationship between diabetes and cardiovascular disease (CVD) 1. Indeed, type 2 diabetes mellitus (T2DM) often occurs in association with cardiovascular risk factors, for example, hypertension, dyslipidemia/hypercholesterolemia, smoking, and obesity which, in turn, are associated with atherosclerosis, ischemic heart disease, and ventricular dysfunction 2. The pathophysiology is increasing in prevalence, primarily because of the obesity pandemic, which considerably increases morbidity and mortality 3,4.

The search for novel therapeutics to tackle cardiometabolic disease is ongoing as current interventions are not entirely successful. Medical practice in CVD care involves platelet-inhibiting and cholesterol-lowering drugs and the cornerstone of T2DM treatment is glycemic control, regulated through, for example, insulin, metformin, thiazolidinediones, exercise, and diet. Importantly, the US Food and Drug Administration stipulates that all new diabetes drugs must be deemed cardiovascular safe 5. This is noteworthy as pharmacological therapy for T2DM has been associated with an increased risk of heart failure, although preclinical duration and the severity of the patient’s diabetes are contributing factors to the cardiovascular impact 6,7.

An ideal therapeutic approach would be to develop drugs targeting both CVD and metabolic disease. Several attempts are ongoing and may involve targeting endoplasmic reticulum (ER) stress or intracellular calcium regulation, as reviewed recently 5. Indeed, ER stress contributes toward atherosclerotic plaque formation 8,9, exaggerated adipose inflammation 10,11, and pancreatic β-cell death 12, and drives mitochondria dysfunction, insulin resistance, and dyslipidemia in hepatocytes 13–15. Similarly, intracellular calcium may trigger macrophage (MΦ) apoptosis, hepatic glucose production, and defective insulin signaling 5, and regulation through calmodulin-dependent protein kinase II has been investigated as an approach that may inhibit cardiometabolic disease 16. Finally, a lucrative therapeutic option may be to promote inflammatory resolution as chronic inflammation drives cardiometabolic pathophysiology 5,17–19. This review describes the role of inflammation in the progression of cardiometabolic disease and how triggering inflammatory resolution through specialized proresolving lipid mediators (SPMs), such as the lipoxins (LXs), may provide a novel and useful therapeutic approach.

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Inflammation and cardiometabolic disease

The central role of inflammation in cardiometabolic pathophysiology is increasingly recognized 5,17–19. Indeed, systemic low-grade inflammation, possibly due to alterations in the gut microbiota and permeability, is a cardinal sign of metabolic disease 20,21. Obesity also inhibits the proliferation and differentiation of preadipocytes and triggers ER unfolded protein response (UPR) stress as a protective mechanism to restore normal function by halting protein translation and stimulating the production of molecular chaperones. However, prolonged UPR stress activates inflammatory pathways and eventually apoptosis and/or necrosis. Furthermore, adipose hypertrophy and resulting hypoxia, hepatic stress responses, and systemic hyperglycemia culminate in adipose inflammation and infiltration of inflammatory M1 MΦs 22,23. MΦ-derived proinflammatory mediators [tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6] are associated with the development of insulin resistance, and the subsequent release of free fatty acids causes systemic lipotoxicity, thus injuring pancreatic β-cells, the cardiovascular system, and indeed organs such as the liver and kidneys 17,22–25. In addition, obesity-induced inflammation disturbs the endocrine function of the adipose tissue, reducing the production of the protective hormone adiponectin, whereas leptin and resistin levels are increased, causing an adipokine imbalance that contributes to disease 17.

Similarly, inflammation plays a critical role in plaque formation and CVD 2,26,27 (Fig. 1). The atherosclerotic process may be initiated by irritants (e.g. hypertension, hyperlipidemia, or smoking) causing endothelial dysfunction. This results in LDL transmigrating through the vascular endothelium and accumulating in the arterial intima, where it is retained by binding to proteoglycans in the extracellular matrix. The rate of lipid accumulation is determined by LDL plasma concentration and the condition of the endothelium. LDL may be oxidized by superoxide released from endothelial cells and the activated endothelium upregulates adhesion molecules [intercellular adhesion molecule (ICAM); vascular cell adhesion molecule 1 (VCAM-1)], resulting in neutrophil recruitment. Neutrophils readily attempt to phagocytose the accumulated lipids and further oxidize LDL (oxLDL) by producing reactive oxygen species (ROS) and metalloproteinases (MMPs). oxLDL is considered a damage-associated molecular pattern molecule (DAMP) as it is recognized by pattern recognition receptors (PRRs), thus triggering a low-grade inflammatory response. The resulting production of proinflammatory cytokines and chemokines (RANTES, monocyte chemotactic protein, macrophage colony-stimulating factor) and increased expression of endothelial adhesion molecules amplify leukocyte recruitment and attract inflammatory monocytes. Monocytes migrate through the intima and differentiate into MΦs, which attempt to clear the inflammatory milieu by phagocytosing both lipid particles and apoptotic cells. MΦs may subsequently exit through the lymphatics or even egress from the plaque into the circulation 28–30, but a large number of cells remain trapped in the intima. The phagocytic ability of the MΦs is eventually exhausted and they transform into lipid-laden ‘foam cells’, which undergo necroptosis and form the necrotic lipid core of the plaque 31,32 (Fig. 1). Other leukocytes, including T-cells, B-cells, and natural killer (NK) cells, are also found in human atherosclerotic plaques 33. Indeed, Th1 cells may drive the M1 MΦ phenotype and foam cell formation, and CD8+ T-cells may promote plaque destabilization through expression of proinflammatory cytokines [TNF-α, interferon-γ (IFN-γ)] and cytotoxic molecules 26,34. Similarly, B-cells produce antibodies that opsonize oxLDL and promote MΦ-mediated phagocytosis. Furthermore, B-cells and neutrophil extracellular traps (NETs) activate dendritic cells (DCs), which, by secreting IL-12, amplify a proatherogenic Th1 response. NK T-cells also promote lesion formation through cytotoxic granzyme B and perforin expression. Regulatory T-cells (Treg) may, in contrast, serve as an anti-inflammatory mediator, inhibiting foam cell formation, and Treg promotes an antiatherogenic lipid profile in hypercholesterolemic mice 35.

Fig. 1

Fig. 1

As the inflammatory milieu drives plaque progression, endothelial cells and foam cells produce fibroblast growth factor and platelet-derived growth factor, which activate smooth muscle cells (SMCs) in the arterial wall, stimulating their proliferation and migration to the intima 2,36. SMCs produce collagens and elastin, which form a fibrous capsule that acts as a ‘barrier’ in advanced atheromata, and therefore, SMC apoptosis may cause detrimental cap thinning 37,38. Furthermore, SMCs may phagocytose lipids and become foam cells themselves 2. As the plaque continues to grow, an adaptive response occurs, whereby the adventia expands, in a process known as ‘remodeling’, which is a compensatory attempt to retain vascular function and leave the arterial lumen open. However, as the plaque buildup continues, the compensatory remodeling reaches its limit and the plaque protrudes into the lumen. Biodynamical and hemodynamic stresses may cause the plaque to rupture and if the necrotic core comes in contact with blood platelets, a thrombus forms and a cardiovascular event may occur. Interestingly, early plaques are more likely to rupture then stable, more advanced plaques protruding into the lumen 27. The plaques that are particularly vulnerable to rupture are localized at sites of turbulent flow and are characterized not necessarily by size per se, but rather by a soft lipid-rich necrotic core surrounded by an inflamed and thin fibrous capsule 39. Indeed, rupture may be a result of fibrous cap thinning because of defective collagen synthesis and/or MMP-mediated collagen degradation and/or insufficient inflammatory resolution 2,27.

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Inflammatory resolution

Inflammation is an intricate and carefully regulated process that is required by the body to maintain health. In health, inflammation consists of two phases: an initial acute phase, followed by a resolving phase. The acute phase is initiated by peptides (cytokines, chemokines) and lipids (prostaglandins, leukotrienes), inducing edema and leukocyte recruitment. Importantly, this phase does not automatically dissipate after the initial injury has been resolved, but rather an active resolution must be initiated 19,40. Inflammatory resolution is regulated by SPMs: the ω3-polyunsaturated fatty acid (PUFA)-derived protectins, resolvins and maresins, and the ω6-PUFA-derived LXA4 and LXB4 19,41,42. In addition, the peptide Annexin A1 (AnxA1) is an important endogenous regulator of inflammatory resolution 43,44. Both LXA4 and AnxA1 activate the FPR2/ALX G-protein coupled receptor, although the LXB4 receptor remains to be identified 19,41,42. Together, these proresolving mediators attenuate neutrophil recruitment, while inducing a proresolving M2 MΦ phenotype, thus promoting MΦ-mediated phagocytosis of apoptotic cells (efferocytosis) and inflammatory resolution 41. Impaired inflammatory resolution may underlie the pathogenesis of chronic inflammatory disorders, such as metabolic syndrome, diabetes, and CVD 45,46. The therapeutic potential of using SPMs to promote resolution and overcome chronic inflammation and disease has therefore been highlighted 8,19,43,47–51.

The chronic inflammation characterizing cardiometabolic pathophysiology may indeed reflect defective resolution 45. However, it is important to note that endogenous resolution is not always impaired. As an example, 30% of obese patients appear to remain ‘metabolically healthy’, that is, lacking metabolic disorders (diabetes, dyslipidemia, hypertension) 52, which may be because of an enhanced endogenous ability to initiate resolution. Similarly, atherosclerotic lesions often undergo partial resolution, characterized by the formation of the fibrous cap that provides a barrier between the prothrombotic plaque and the platelets in the blood stream, and thus most atherosclerotic plaques do not cause acute vascular disease 53. It is therefore possible that cardiometabolic morbidity and mortality may be reduced by strengthening the patients’ endogenous ability to resolve inflammation. Importantly, such therapeutic approaches would likely have few side effects and provide long-term safety with respect to CVD. The ω3-PUFA-derived SPMs attenuate obesity-induced adipose inflammation and related liver disease 54–58 as well as many features of CVD (for review articles, see 22,40,59,60). Similarly, AnxA1 correlates with reduced adipose inflammation and protects against nonalcoholic steatohepatitis 61,62. Furthermore, AnxA1 may protect against myocardial infarction 63 and when using collagen IV-targeted nanoparticles to deliver Ac2-26 (the N-terminal derived peptide of AnxA1) to the advanced atherosclerotic lesions of fat-fed Ldlr−/− mice, Ac2-26 promotes plaque stability while decreasing oxidative stress and plaque necrosis 64. Recent evidence also shows the therapeutic potential of LXs in cardiometabolic disease, as outlined below.

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Lipoxins in atherosclerosis and cardiovascular disease

Inflammation plays a crucial role in atherosclerotic plaque formation and CVD, as outlined above, and the therapeutic potential of LXs has been highlighted as they may promote the resolution of atherosclerotic plaques and increase plaque stability 2,19,27,40,65 (Fig. 1). Indeed, patients with symptomatic peripheral artery disease have lower levels of aspirin-triggered LXs 66 and chronic heart failure is associated with reduced LX levels in plasma and urine 67. Interestingly, SPMs derived from perivascular adipose tissue may influence the inflammatory resolution of atherosclerotic plaques 68. Furthermore, LXs reduce reperfusion-associated vascular inflammation 69 and protect cardiomyocytes by modulating potassium channels 70 and activating p38 MAPK pathways and nuclear translocation of Nrf2, which induces the release of the protective hemeoxygenase-1 71.

An initiating factor in the atherosclerotic process is the activation of endothelial cells, which upregulate adhesion molecules utilized by leukocytes to enter the arterial intima. LXs inhibit angiogenic pathways, including endothelial proliferation and activation 72–75. LXs reduce P-selectin expression in human aortic endothelial cells 76,77 and attenuate P-selectin-mediated neutrophil–endothelial interactions 78. LXs also inhibit neutrophil chemotaxis, adhesion, and transmigration 79, and reduce proinflammatory cytokine secretion 80 and ROS production 79,81,82. Finally, a recent study showed that LXs attenuate neutrophil NET formation 83. NETs play a critical role in atherosclerosis by activating DCs to produce IL-12, thus driving Th1 cellular responses 84, for instance, IFN-γ production that stimulates an M1 MΦ phenotype and foam cell formation 85. Indeed, the LX-mediated attenuation of NET formation is worthy of further investigation.

The importance of the monocyte phenotype in the atherosclerotic process has received considerable attention, although the knowledge of the field is continuously evolving. The murine monocytes are commonly classified as inflammatory Ly6Chi versus the less inflammatory Ly6lo. Interestingly, the inflammatory Ly6Chi monocytes appear to be particularly important in the onset of atherosclerosis, although the maximal inhibition of atherosclerosis is achieved when blocking all monocyte recruitment 86. Importantly, similar subsets of monocytes exist in humans, often characterized as classical (CD14++CD16), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) subsets, where the classical CD14+ +CD16 correspond to the Ly6Chi subset, although it is not yet clear how these contribute toward the atherosclerotic process in humans. It is noteworthy that LXs specifically attract ‘anti-inflammatory’ monocytes to inflammatory sites, which are characterized by reduced ROS production as they migrate to the tissue 87, and LXs decrease monocyte IL-1β and calcium influx 88.

Similar to the monocytes, MΦs may be subphenotyped into several classes, showing inflammatory, proresolving, and/or wound-healing properties depending on their phenotype. MΦs are commonly characterized as ‘inflammatory M1’ versus ‘anti-inflammatory M2’, where the former are proatherogenic and the latter are antiatherogenic. Admittedly, this is an oversimplification as several other MΦ phenotypes are of critical importance to the atherosclerotic process and inflammation 26,27,32. However, for this review, we will refer to the M1/M2 nomenclature. One of the cardinal effects of LXs is that they promote a ‘proresolving’ M2 MΦ phenotype, which correlate with decreased production of proinflammatory mediators, for example, TNF-α, IL-6, and nuclear factor (NF)-κβ activation, whereas the anti-inflammatory milieu is promoted by increased TGF-β1 and IL-10 levels 62,80,89–91. A critical result of this phenotypic switch is improved efferocytosis as LXs remodel the MΦ cytoskeleton to promote their engulfment of apoptotic cells 92–95. Finally, LXs reduce MΦ apoptosis 96, which may enable the cells to perform their cellular functions for longer. As impaired efferocytosis and premature MΦ necroptosis are proatherogenic effects, the LX-mediated shift in the MΦ phenotype and function is noteworthy. LXs may also act as antiatherogenic agents by promoting anti-inflammatory characteristics of other leukocytes. Indeed, LXs enhance CCR5 expression on apoptotic neutrophils and T-cells, which promotes inflammatory resolution by acting as a decoy receptor for CCL3, CCL4, and CCL5, thus terminating chemokine signaling 97. Furthermore, LXs decrease the proliferation, and IgG and IgM production of human memory B-cells, thereby downregulating NF-κB p65 nuclear translocation in an ALX/FPR2-dependent manner 98, which may reduce oxLDL opsonization and foam cell formation.

The liver plays a critical role in the atherosclerotic process as hepatic C-reactive protein increases the endothelial expression of adhesion molecules, thus amplifying the inflammatory response. Cholesterol metabolism is closely interlinked with CVD and statins promote a favorably LDL-cholesterol and HDL-cholesterol ratio, which attenuates cardiovascular pathophysiology. Interestingly, a recent study by Demetz et al. 99 shows that the arachidonic acid metabolome is an important regulator of cholesterol homeostasis. Aspirin-induced LXs increase hepatic expression of the bile salt export pump ABCB11, which translates into enhanced reverse cholesterol transport, a key function of HDL. LX mimetics also lower plasma LDL-cholesterol 99 and reduce obesity-induced elevation of serum alanine aminotransferase and hepatic steatosis through reduction of adipose inflammation and a subsequent increase in AnxA1 62. Furthermore, LXs enhance organ function in murine liver transplantation, decreasing IFN-γ while increasing IL-10 100,101.

If an atherosclerotic plaque ruptures, a thrombus may form and plaque stability is therefore of great importance to the clinical care of patients. Inflammatory mediators regulate the matrix-degrading proteinases that contribute toward the dissolution of interstitial collagen, thus thinning and weakening the fibrous cap 102. LXs inhibit IL-1β-induced IL-6, IL-8, and MMP-3 production in human fibroblasts and furthermore enhance the synthesis of MMP inhibitors 103, which may promote plaque stabilization. Furthermore, LXs modulate platelet-derived growth factor-stimulated migration of vascular SMCs isolated from human saphenous veins 66. Interestingly, the pluripotent FPR2/ALX receptor may play a dual role in atherosclerosis, promoting disease progression through proatherogenic effects on bone marrow-derived cells, but increasing plaque stability by promoting SMC collagen synthesis and cross-linking 104. In this context, it is worth highlighting that the characteristic expression of SMC and MΦ surface markers may be altered in the pathophysiological milieu of the atherosclerotic plaque so that MΦs may express SMC markers (e.g. α-actin and SM22α) and SMCs may express traditional MΦ markers (e.g. CD68 and Mac2) 2. This is noteworthy when interpreting the literature of the field as SMCs and MΦs may have been misidentified in previous studies.

Finally, circulating bacteria may contribute toward atherogenesis. For instance, the periodontal pathogen Porphyromonas gingivalis causes platelet aggregation and contributes toward CVD in mice 105–110 and the bacterium has been found in human atherosclerotic plaques 111,112. In this context, it is noteworthy that LXs reduce P. gingivalis-induced neutrophil–platelet aggregation and ROS production in human whole blood by downregulating neutrophil CD11b/CD18 expression and its high-affinity epitope 82. Furthermore, LXs inhibit P. gingivalis-induced neutrophil influx, COX-2 expression, and PGE2 secretion in the periodontal cavity of mice, without promoting further spread of the infection 113. In addition, LXs may act as a vasodilator by promoting endothelial release of prostacyclin and nitric oxide, while inhibiting ROS production 114–116, highlighting that LXs may have therapeutic potential in attenuating acute cardiovascular events.

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Lipoxins in metabolism and adipose inflammation

It is well-established that white adipose tissue (WAT) is not merely an insulating energy store but also an endocrine organ regulating appetite, glucose and lipid metabolism, blood pressure, inflammation, and immune function 117. As outlined in the introduction, prolonged obesity causes a state of systemic low-grade inflammation, resulting in insulin resistance, metabolic syndrome, and pathologies such as T2DM, atherosclerosis, and nonalcoholic fatty liver disease 118. As detailed below, LXs promotes resolution of adipose inflammation and protects against obesity-induced metabolic disease (for reviews see 17,40,51). Importantly, the FPR2/ALX receptor is expressed in both human and mouse adipose tissue 57,119.

LXs promote the resolution of adipose inflammation by inducing an M1-to-M2 MΦ phenotype switch. We first showed this in a model of age-associated adipose inflammation 119, representing a chronic, low-grade inflammation similar to obesity and T2DM-associated inflammation 120. In this model, LX attenuated IL-6 and increased IL-10 expression 119. The altered cytokine milieu correlated with increased glucose transporter type 4 (GLUT-4) and insulin receptor substrate-1 (IRS-1) expression, suggesting improved insulin sensitivity. In-vitro studies confirmed that LX rescued MΦ-induced desensitization to insulin-stimulated signaling and restored 3H-glucose uptake in cultured adipocytes. This was associated with preservation of AKT activation and reduced secretion of proinflammatory cytokines, including TNF-α 119.

Similarly, in a model of diet-induced obesity, interventional treatment with LXs promotes an adipose M1-to-M2 MΦs phenotype switch, inhibiting CD11c+ M1 MΦs and TNF-α, while restoring CD206+ M2 MΦs and increasing AnxA1 production 62. Early studies have suggested that LXs might mediate protection against disease by inducing the production of the protective hormone adiponectin 57. However, increased adiponectin levels appear to be a consequence of an ‘overall’ improved adipose milieu, rather than a direct stimulation, as LX-mediated protection is sustained in Adiponectin−/− mice 62. Furthermore, LXs did not induce adiponectin production in cultured 3T3-L1 adipocytes 62. Interestingly, LXs did not enhance obesity-induced impairment of glucose tolerance in the obese C57BL/6J mice, indicating that the lipid may not affect pancreatic insulin function 62. However, LXs reduced fasting glucose in Adiponectin−/− mice 62 and rescued 3H-glucose uptake in cultured adipocytes 119, suggesting that the lipid may exert some modulation of insulin resistance. In the experimental obesity model, LX-induced restoration of WAT function resulted in protection against systemic kidney and liver disease 62. Importantly, LX-mediated protection against obesity-induced pathologies occurred without affecting total body weight 62, suggesting that LXs may promote a ‘metabolically healthy phenotype’, which, in humans, can provide protection against, for example, cardiometabolic pathophysiology and reduce obesity-related mortality 3,4,121, although this remains to be investigated.

It is important to highlight that WAT is comprised of a heterogeneous composition of cells: 60% adipocytes and a 40% stromal-vascular compartment, the latter composed of preadipocytes, leukocytes, fibroblasts, and endothelial cells 122. In the scientific field, particular focus has been directed toward MΦs as critical effector cells initiating WAT inflammation and insulin resistance, and indeed MΦ depletion attenuates obesity-induced insulin resistance 23,25,123–125. However, T-cells, B-cells, NK-cells, and DCs are also important regulators of adipose inflammation 126 and neutrophils mediate insulin resistance in obese mice 127. It is noteworthy that in addition to their well-established actions on leukocytes 49, LXs affect numerous cell types, including adipocytes 119. Indeed, LXA4-mediated attenuation of WAT inflammation occurs through modulation of both MΦ and adipocyte cell signaling 119 (Fig. 2). As evidence of the latter, cultured 3T3-L1 adipocytes express the murine equivalent of the FPR2/ALX receptor Fpr3/Fpr-rs2 119 and when stimulated with LXA4, adipocytes resist TNF-α induced impairment of insulin-stimulated GLUT-4 translocation 119. Again, a key mechanism involves LX-mediated restoration of AKT activation: a ubiquitous serine/threonine kinase regulating metabolism and apoptosis. Insulin-induced AKT phosphorylation enables translocation of GLUT-4 to the plasma membrane and thus cellular glucose uptake. Interestingly, when LXA4 mediates protection through MΦs, AKT phosphorylation is restored both at the Serine473 and at the Threonine308 site 119. However, adipocytes incubated directly with LXA4 only show restored phosphorylation at the threonine 308 site, indicating a specific signaling pathway 119. Finally, it is quite possible that LXs, in addition to modulating MΦs and adipocytes, might affect additional WAT cells, both of myeloid and of nonmyeloid origin, for example, T-cell subsets, B-cells, fibroblasts, and possibly also preadipocyte differentiation. Studies investigating these possibilities would be valuable to the scientific community.

Fig. 2

Fig. 2

Interesting, our recent findings indicate that LXs may modulate obesity-induced adipose autophagy 62, which may impact adipose inflammation and metabolic pathophysiology. The role of autophagy in adipose inflammation is complex, but the current consensus is that chronic obesity causes excessive activation of autophagy in the adipose tissue, which correlates with increased cell death and adipose inflammation 128–130. Obesity is associated with enhanced levels of WAT autophagy, as evidenced from decreased p62 and LC3-II levels, suggesting high autophagy flux and enhanced degradation of the proteins. LXs restore obesity-induced attenuation of p62 and LC3-II protein to the levels observed in lean mice 62. The mechanisms appear to be mTOR and AMPK independent 62, but it is unknown whether LXs affect autophagosome maturation (fusion of autophagosomes with lysosome). Thus, future studies are needed to detail the molecular mechanisms involved in LX-mediated regulation of autophagy and its significance to adipose inflammation. In addition, it is noteworthy that p62/SQSTM1 has been identified as one of the key proteins that promote lipid metabolism and limit inflammation in the recently identified ‘metabolically activated’ MΦ (mMe-MΦ) 131. Activation of p62 results in inhibition of NF-κβ and thus limits inflammation. The LX-mediated restoration of p62 activity may thus not only interlink with autophagy, but may promote the anti-inflammatory mMe-MΦ population, although this remains to be further investigated in future work.

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Conclusion

The prevalence of cardiometabolic disease is increasing, with severe socioeconomic implications. Inflammation is a common denominator is both metabolic and cardiovascular disease and promoting inflammatory resolution may thus be a useful therapeutic approach. The endogenously produced LXs likely have few side effects and, by promoting inflammatory resolution in adipose tissue and atherosclerotic plaques, while inhibiting angiogenic pathways and neutrophil–platelet aggregation, LXs may have therapeutic potential in cardiometabolic disease.

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Acknowledgements

E.B. is funded by a Marie Curie International Outgoing Fellowship (GA-2011-301803).

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Conflicts of interest

There are no conflicts of interest.

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References

1. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, et al.. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56:1113–1132.
2. Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol 2015; 209:13–22.
3. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013; 309:71–82.
4. Van der AD, Nooyens AC, van Duijnhoven FJ, Verschuren MM, Boer JM. All-cause mortality risk of metabolically healthy abdominal obese individuals: the EPIC-MORGEN study. Obesity 2014; 22:557–564.
5. Fredman G, Ozcan L, Tabas I. Common therapeutic targets in cardiometabolic disease. Sci Transl Med 2014; 6:239ps5.
6. Maru S, Koch GG, Stender M, Clark D, Gibowski L, Petri H, et al.. Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting. Diabetes care 2005; 28:20–26.
7. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab 2011; 14:575–585.
8. Zhou AX, Tabas I. The UPR in atherosclerosis. Semin Immunopathol 2013; 35:321–332.
9. Tabas I. The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ Res 2010; 107:839–850.
10. Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2012; 2:799.
11. Jiao P, Ma J, Feng B, Zhang H, Diehl JA, Chin YE, et al.. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKbeta pathways. Obesity 2011; 19:483–491.
12. Papa FR. Endoplasmic reticulum stress, pancreatic beta-cell degeneration, and diabetes. Cold Spring Harb Perspect Med 2012; 2:a007666.
13. Li H, Zhou B, Liu J, Li F, Li Y, Kang X, et al.. Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2alpha-dependent manner. Cell cycle 2015; 14:1893–1907.
14. Arruda AP, Pers BM, Parlakgul G, Güney E, Inouye K, Hotamisligil GS. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med 2014; 20:1427–1435.
15. Mollica MP, Lionetti L, Putti R, Cavaliere G, Gaita M, Barletta A. From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammation. Nutr Metab Cardiovasc Dis 2011; 21:222–230.
16. Ozcan L, Tabas I. CaMKII in cardiometabolic disease. Aging 2014; 6:430–431.
17. Borgeson E, Sharma K. Obesity, immunomodulation and chronic kidney disease. Curr Opin Pharmacol 2013; 13:618–624.
18. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 2013; 339:166–172.
19. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014; 510:92–101.
20. Chassaing B, Gewirtz AT. Gut microbiota, low-grade inflammation, and metabolic syndrome. Toxicol Pathol 2014; 42:49–53.
21. Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M, Colecchia A. Gut microbiota and metabolic syndrome. World J Gastroenterol 2014; 20:16079–16094.
22. Gonzalez-Periz A, Claria J. Resolution of adipose tissue inflammation. ScientificWorldJournal 2010; 10:832–856.
23. McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity 2014; 41:36–48.
24. Cusi K. The role of adipose tissue and lipotoxicity in the pathogenesis of type 2 diabetes. Curr Diab Rep 2010; 10:306–315.
25. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72:219–246.
26. Cochain C, Zernecke A. Macrophages and immune cells in atherosclerosis: recent advances and novel concepts. Basic Res Cardiol 2015; 110:34.
27. Libby P, Tabas I, Fredman G, Fisher EA. Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 2014; 114:1867–1879.
28. Feig JE, Parathath S, Rong JX, Mick SL, Vengrenyuk Y, Grauer L, et al.. Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 2011; 123:989–998.
29. Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, Liu J, et al.. HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci USA 2011; 108:7166–7171.
30. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA 2004; 101:11779–11784.
31. Schrijvers DM, De Meyer GR, Kockx MM, Herman AG, Martinet W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25:1256–1261.
32. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013; 13:709–721.
33. Grivel JC, Ivanova O, Pinegina N, Blank PS, Shpektor A, Margolis LB, Vasilieva E. Activation of T lymphocytes in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2011; 31:2929–2937.
34. Methe H, Brunner S, Wiegand D, Nabauer M, Koglin J, Edelman ER. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol 2005; 45:1939–1945.
35. Klingenberg R, Gerdes N, Badeau RM, Gisterå A, Strodthoff D, Ketelhuth DF, et al.. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest 2013; 123:1323–1334.
36. Millette E, Rauch BH, Defawe O, Kenagy RD, Daum G, Clowes AW. Platelet-derived growth factor-BB-induced human smooth muscle cell proliferation depends on basic FGF release and FGFR-1 activation. Circ Res 2005; 96:172–179.
37. Clarke MC, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, Bennett MR. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med 2006; 12:1075–1080.
38. Clarke MC, Littlewood TD, Figg N, Maguire JJ, Davenport AP, Goddard M, Bennett MR. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res 2008; 102:1529–1538.
39. Yla-Herttuala S, Bentzon JF, Daemen M, Falk E, Garcia-Garcia HM, Herrmann J, et al.. ESC Working Group of Atherosclerosis and Vascular Biology. Stabilization of atherosclerotic plaques: an update. Eur Heart J 2013; 34:3251–3258.
40. Romano M, Cianci E, Simiele F, Recchiuti A. Lipoxins and aspirin-triggered lipoxins in resolution of inflammation. Eur J Pharmacol 2015; 760:49–63.
41. Maderna P, Godson C. Lipoxins: resolutionary road. Br J Pharmacol 2009; 158:947–959.
42. Serhan CN, Chiang N, Dalli J. The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. Semin Immunol 2015; 27:200–215.
43. Perretti M, Dalli J. Exploiting the annexin A1 pathway for the development of novel anti-inflammatory therapeutics. Br J Pharmacol 2009; 158:936–946.
44. Perretti M, D’Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol 2009; 9:62–70.
45. Spite M, Claria J, Serhan CN. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab 2014; 19:21–36.
46. Borgeson E, Godson C. Molecular circuits of resolution in renal disease. ScientificWorldJournal 2010; 10:1370–1385.
47. Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 2013; 17:860–872.
48. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 2014; 13:465–476.
49. Serhan CN. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 2007; 25:101–137.
50. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol 2005; 6:1191–1197.
51. Borgeson E, Godson C. Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications. Front Immunol 2012; 3:318.
52. Badoud F, Perreault M, Zulyniak MA, Mutch DM. Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals. FASEB J 2014; 29:748–758.
53. Virmani R, Burke AP, Kolodgie FD, Farb A. Vulnerable plaque: the pathology of unstable coronary lesions. J Interv Cardiol 2002; 15:439–446.
54. Gonzalez-Periz A, Horrillo R, Ferre N, Gronert K, Dong B, Morán-Salvador E, et al.. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J 2009; 23:1946–1957.
55. Hellmann J, Tang Y, Kosuri M, Bhatnagar A, Spite M. Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice. FASEB J 2011; 25:2399–2407.
56. Neuhofer A, Zeyda M, Mascher D, Itariu BK, Murano I, Leitner L, et al.. Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation. Diabetes 2013; 62:1945–1956.
57. Claria J, Dalli J, Yacoubian S, Gao F, Serhan CN. Resolvin D1 and resolvin D2 govern local inflammatory tone in obese fat. J Immunol 2012; 189:2597–2605.
58. Titos E, Rius B, Gonzalez-Periz A, López-Vicario C, Morán-Salvador E, Martínez-Clemente M, et al.. Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. J Immunol 2011; 187:5408–5418.
59. Titos E, Claria J. Omega-3-derived mediators counteract obesity-induced adipose tissue inflammation. Prostaglandins Other Lipid Mediat 2013; 107:77–84.
60. Lopez-Vicario C, Rius B, Alcaraz-Quiles J, García-Alonso V, Lopategi A, Titos E, Clària J. Pro-resolving mediators produced from EPA and DHA: overview of the pathways involved and their mechanisms in metabolic syndrome and related liver diseases. Eur J Pharmacol 2015. [Epub ahead of print].
61. Locatelli I, Sutti S, Jindal A, Vacchiano M, Bozzola C, Reutelingsperger C, et al.. Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice. Hepatology 2014; 60:531–544.
62. Börgeson E, Johnson AM, Lee YS, Till A, Syed GH, Ali-Shah ST, et al.. Lipoxin A attenuates obesity-induced adipose inflammation and associated liver and kidney disease. Cell Metab 2015; 22:125–137.
63. Qin C, Yang YH, May L, Gao X, Stewart AG, Tu Y, et al.. Cardioprotective potential of annexin-A1 mimetics in myocardial infarction. Pharmacol Ther 2015; 148:47–65.
64. Fredman G, Kamaly N, Spolitu S, Milton J, Ghorpade D, Chiasson R, et al.. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med 2015; 7:275ra220.
65. Back M, Weber C, Lutgens E. Regulation of atherosclerotic plaque inflammation. J Intern Med 2015, doi: 10.1111/joim.12367 [Epub ahead of print].
66. Ho KJ, Spite M, Owens CD, Lancero H, Kroemer AH, Pande R, et al.. Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Am J Pathol 2010; 177:2116–2123.
67. Reina-Couto M, Carvalho J, Valente MJ, Vale L, Afonso J, Carvalho F, et al.. Impaired resolution of inflammation in human chronic heart failure. Eur J Clin Invest 2014; 44:527–538.
68. Claria J, Nguyen BT, Madenci AL, Ozaki CK, Serhan CN. Diversity of lipid mediators in human adipose tissue depots. Am J Physiol Cell Physiol 2013; 304:C1141–1149.
69. Brancaleone V, Gobbetti T, Cenac N, le Faouder P, Colom B, Flower RJ, et al.. A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation. Blood 2013; 122:608–617.
70. Chen XQ, Wu SH, Zhou Y, Tang YR. Involvement of K+ channel-dependant pathways in lipoxin A4-induced protective effects on hypoxia/reoxygenation injury of cardiomyocytes. Prostaglandins Leukot Essent Fatty Acids 2013; 88:391–397.
71. Chen XQ, Wu SH, Zhou Y, Tang YR. Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex. PLoS One 2013; 8:e67120.
72. Baker N, O’Meara SJ, Scannell M, Maderna P, Godson C. Lipoxin A4: anti-inflammatory and anti-angiogenic impact on endothelial cells. J Immunol 2009; 182:3819–3826.
73. Cezar-de-Mello PF, Vieira AM, Nascimento-Silva V, Villela CG, Barja-Fidalgo C, Fierro IM. ATL-1, an analogue of aspirin-triggered lipoxin A4, is a potent inhibitor of several steps in angiogenesis induced by vascular endothelial growth factor. Br J Pharmacol 2008; 153:956–965.
74. Fierro IM, Kutok JL, Serhan CN. Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15 R-lipoxin A(4) and lipoxin A(4). J Pharmacol Exp Ther 2002; 300:385–392.
75. Jin Y, Arita M, Zhang Q, Saban DR, Chauhan SK, Chiang N, et al.. Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators. Invest Ophthalmol Vis Sci 2009; 50:4743–4752.
76. Merched AJ, Ko K, Gotlinger KH, Serhan CN, Chan L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J 2008; 22:3595–3606.
77. Scalia R, Gefen J, Petasis NA, Serhan CN, Lefer AM. Lipoxin A4 stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: role of P-selectin. Proc Natl Acad Sci USA 1997; 94:9967–9972.
78. Papayianni A, Serhan CN, Brady HR. Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. J Immunol 1996; 156:2264–2272.
79. Chiang N, Serhan CN, Dahlen SE, Drazen JM, Hay DW, Rovati GE, et al.. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev 2006; 58:463–487.
80. Jozsef L, Zouki C, Petasis NA, Serhan CN, Filep JG. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-kappa B and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc Natl Acad Sci USA 2002; 99:13266–13271.
81. Levy BD, Fokin VV, Clark JM, Wakelam MJ, Petasis NA, Serhan CN. Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a ‘stop’ signaling switch for aspirin-triggered lipoxin A4. FASEB J 1999; 13:903–911.
82. Borgeson E, Lonn J, Bergstrom I, Brodin VP, Ramström S, Nayeri F, et al.. Lipoxin A(4) inhibits Porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression. Infect Immun 2011; 79:1489–1497.
83. Tibrewal S, Ivanir Y, Sarkar J, Nayeb-Hashemi N, Bouchard CS, Kim E, Jain S. Hyperosmolar stress induces neutrophil extracellular trap formation: implications for dry eye disease. Invest Ophthalmol Vis Sci 2014; 55:7961–7969.
84. Ait-Oufella H, Taleb S, Mallat Z, Tedgui A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol 2011; 31:969–979.
85. Panousis CG, Zuckerman SH. Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma. J Lipid Res 2000; 41:75–83.
86. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, et al.. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117:185–194.
87. Maddox JF, Serhan CN. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J Exp Med 1996; 183:137–146.
88. Wang J, Huang Y, Huang Y, Zhou J, Liu X. Effect of lipoxin A(4) on IL-1beta production of monocytes and its possible mechanism in severe preeclampsia. J Huazhong Univ Sci Technolog Med Sci 2010; 30:767–770.
89. Huang YH, Wang HM, Cai ZY, Xu FY, Zhou XY. Lipoxin A4 inhibits NF-kappaB activation and cell cycle progression in RAW264.7 cells. Inflammation 2014; 37:1084–1090.
90. Kure I, Nishiumi S, Nishitani Y, Tanoue T, Ishida T, Mizuno M, et al.. Lipoxin A(4) reduces lipopolysaccharide-induced inflammation in macrophages and intestinal epithelial cells through inhibition of nuclear factor-kappaB activation. J Pharmacol Exp Ther 2010; 332:541–548.
91. Vasconcelos DP, Costa M, Amaral IF, Barbosa MA, Águas AP, Barbosa JN. Modulation of the inflammatory response to chitosan through M2 macrophage polarization using pro-resolution mediators. Biomaterials 2015; 37:116–123.
92. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 2007; 447:869–874.
93. Mitchell S, Thomas G, Harvey K, Cottell D, Reville K, Berlasconi G, et al.. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J Am Soc Nephrol 2002; 13:2497–2507.
94. Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR, et al.. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol 2000; 164:1663–1667.
95. Reville K, Crean JK, Vivers S, Dransfield I, Godson C. Lipoxin A4 redistributes myosin IIA and Cdc42 in macrophages: implications for phagocytosis of apoptotic leukocytes. J Immunol 2006; 176:1878–1888.
96. Prieto P, Cuenca J, Traves PG, Fernández-Velasco M, Martín-Sanz P, Boscá L. Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways. Cell Death Differ 2010; 17:1179–1188.
97. Ariel A, Fredman G, Sun YP, Kantarci A, Van Dyke TE, Luster AD, Serhan CN. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol 2006; 7:1209–1216.
98. Ramon S, Bancos S, Serhan CN, Phipps RP, Lipoxin A. (4) modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism. Eur J Immunol 2014; 44:357–369.
99. Demetz E, Schroll A, Auer K, Heim C, Patsch JR, Eller P, et al.. The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism. Cell Metab 2014; 20:787–798.
100. Liao W, Zeng F, Kang K, Qi Y, Yao L, Yang H, et al.. Lipoxin A4 attenuates acute rejection via shifting TH1/TH2 cytokine balance in rat liver transplantation. Transplant Proc 2013; 45:2451–2454.
101. Levy BD, Zhang QY, Bonnans C, Primo V, Reilly JJ, Perkins DL, et al.. The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection. Prostaglandins Leukot Essent Fatty Acids 2011; 84:43–50.
102. Libby P. Collagenases and cracks in the plaque. J Clin Invest 2013; 123:3201–3203.
103. Sodin-Semrl S, Taddeo B, Tseng D, Varga J, Fiore S. Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. J Immunol 2000; 164:2660–2666.
104. Petri MH, Laguna-Fernandez A, Gonzalez-Diez M, Paulsson-Berne G, Hansson GK, Bäck M, et al.. The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability. Cardiovasc Res 2015; 105:65–74.
105. Miyakawa H, Honma K, Qi M, Kuramitsu HK. Interaction of Porphyromonas gingivalis with low-density lipoproteins: implications for a role for periodontitis in atherosclerosis. J Periodontal Res 2004; 39:1–9.
106. Chun YH, Chun KR, Olguin D, Wang HL. Biological foundation for periodontitis as a potential risk factor for atherosclerosis. J Periodontal Res 2005; 40:87–95.
107. Gibson FC 3rd, Hong C, Chou HH, Yumoto H, Chen J, Lien E, et al.. Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004; 109:2801–2806.
108. Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 2002; 105:861–867.
109. Seymour GJ, Ford PJ, Cullinan MP, Leishman S, Yamazaki K. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect 2007; 13 (Suppl 4):3–10.
110. Gibson FC 3rd, Yumoto H, Takahashi Y, Chou HH, Genco CA. Innate immune signaling and Porphyromonas gingivalis-accelerated atherosclerosis. J Dent Res 2006; 85:106–121.
111. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification of periodontal pathogens in atheromatous plaques. J Periodontol 2000; 71:1554–1560.
112. Dorn BR, Dunn WA Jr., Progulske-Fox A. Invasion of human coronary artery cells by periodontal pathogens. Infect Immun 1999; 67:5792–5798.
113. Pouliot M, Clish CB, Petasis NA, Van Dyke TE, Serhan CN. Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 2000; 39:4761–4768.
114. Brezinski ME, Gimbrone MA Jr, Nicolaou KC, Serhan CN. Lipoxins stimulate prostacyclin generation by human endothelial cells. FEBS Lett 1989; 245:167–172.
115. Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J Exp Med 2004; 200:69–78.
116. Nascimento-Silva V, Arruda MA, Barja-Fidalgo C, Fierro IM. Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Thromb Haemost 2007; 97:88–98.
117. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89:2548–2556.
118. Shore SA. Obesity, airway hyperresponsiveness, and inflammation. J Appl Physiol 2010; 108:735–743.
119. Börgeson E, McGillicuddy FC, Harford KA, Corrigan N, Higgins DF, Maderna P, et al.. Lipoxin A4 attenuates adipose inflammation. FASEB J 2012; 26:4287–4294.
120. Cevenini E, Caruso C, Candore G, Capri M, Nuzzo D, Duro G, et al.. Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches. Curr Pharm Des 2010; 16:609–618.
121. Badoud F, Perreault M, Zulyniak MA, Mutch DM. Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals. FASEB J 2015; 29:748–758.
122. Wood IS, de Heredia FP, Wang B, Trayhurn P. Cellular hypoxia and adipose tissue dysfunction in obesity. Proc Nutr Soc 2009; 68:370–377.
123. Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al.. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006; 116:115–124.
124. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 2007; 56:16–23.
125. Lumeng CN, Deyoung SM, Saltiel AR. Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 2007; 292:E166–174.
126. Mraz M, Haluzik M. The role of adipose tissue immune cells in obesity and low-grade inflammation. J Endocrinol 2014; 222:R113–127.
127. Talukdar S, Oh da Y, Bandyopadhyay G, Li D, Xu J, McNelis J, et al.. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012; 18:1407–1412.
128. Martinez J, Verbist K, Wang R, Green DR. The relationship between metabolism and the autophagy machinery during the innate immune response. Cell Metab 2013; 17:895–900.
129. Stienstra R, Haim Y, Riahi Y, Netea M, Rudich A, Leibowitz G. Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes. Diabetologia 2014; 57:1505–1516.
130. Cummins TD, Holden CR, Sansbury BE, Gibb AA, Shah J, Zafar N, et al.. Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab 2014; 307:E262–277.
131. Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, et al.. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 2014; 20:614–625.
Keywords:

cardiometabolic disease; inflammation; lipoxin; resolution; specialized proresolving lipid mediators

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