Lipoxin A4 Regulates M1/M2 Macrophage Polarization via FPR2-IRF Pathway

Lipoxin A4 (LXA4) has been shown to have anti-inflammatory activity, but its underlying molecular mechanisms are not clear. Herein, our team investigated the potential role of LXA4 in the macrophage polarisation and elucidated its possible molecular mechanism. The RAW264.7 macrophage cell line was subjected to pre-treatment with LXA4 with or without lipopolysaccharides (LPS) and interleukin-4 (IL-4). In cultured macrophages, LXA4 inhibits LPS-induced inflammatory polarization, thereby decreasing the release of proinflammation cell factors (IL-1β, IL-6, TNF-α) and increasing the release of antiinflammation cytokines (IL-4 and IL-10). Notably, the inhibitory effect of LXA4 on inflammation macrophage polarisation was related to the downregulation of p-NF-κB p65 and IRF5 activity, thereby downregulating LPS-induced phenotypic and functional polarization of macrophage M1 via the FPR2/IRF5 signaling pathway. Moreover, LXA4 also promotes the IL-4-induced polarization of M2 macrophages by promoting the FPR2/IRF4 signaling pathway. Therefore, Lipoxin A4 regulates M1/M2 polarization of macrophages via FPR2-IRF pathway.

An investigation of the association between lipoxin A4 levels and metabolic syndrome parameters in patients with metabolic syndrome

Aim: Metabolic syndrome (MS) is a significant public health problem and has the potential to increase the risk of developing cardiovascular diseases (CVD), the risk of type 2 Diabetes Mellitus (T2DM), the risk of stroke and the risk of a heart attack. MS has recently been considered an inflammatory disease. Lipoxins (LXs) are, on the other hand, bioactive lipid molecules synthesized from arachidonic acid (AA) and show potent anti-inflammatory and pro-resolving activities in vivo and in vitro conditions. In this study, we aimed to evaluate serum levels of LXA4 in MS patients and explore the relationship of serum LXA4 levels with MS components [waist circumference, blood pressure, serum high-density lipoprotein (HDL), and triglyceride (TG) levels]. Material and Method: In this study, the sample was composed of 39 patients diagnosed with MS and 32 healthy age- and sex-matched individuals. We measured serum LXA4 levels adopting the enzyme-linked immunosorbent assay (ELISA) method with “Human Lipoxin A4 ELISA Kit”. While collecting the blood samples from the subjects, we noted their ages, sex, physical examination findings, and anthropometric measurements [height, weight, waist circumference, and body mass index (BMI)]. Additionally, we obtained their serum TG, low-density lipoprotein (LDL), HDL, glucose, and cholesterol levels. Results: While we could not find any significant differences between the groups by age and sex (p>0.05), the groups significantly differed by weight, waist circumference, BMI, systolic blood pressure, diastolic blood pressure, TG, HDL, and FBG (p<0.05 for TG; p<0.001 for others). Moreover, serum levels of LXA4 significantly differed between the groups (p<0.05). Within-group comparisons showed that while serum levels of LXA4 significantly differed between male subjects (p=0.01), it was not the case for females (p>0.05). In both groups, there were negative correlations between serum LXA4 levels and waist circumference (r=-0.368 p=0.02). Yet, we found such an association only among male patients (r=-0.516 p=0.02). Conclusion: Overall, we found serum LXA4 levels to be significantly low in MS patients (p<0.05). Yet, it still needs to be elucidated whether this impairment is a cause or a result of MS. Finally, we discovered this impairment and its significant correlations with some MS parameters to be only in male patients, suggesting that serum LXA4 levels may vary by sex in MS patients.

Dysregulation of prostaglandins, leukotrienes and lipoxin A4 in bronchiectasis

IntroductionBronchiectasis is characterised by excessive neutrophilic inflammation. Lipid mediators such as prostaglandins and leukotrienes have crucial roles in the inflammatory response. Further characterisation of these lipids and understanding the interplay of anti-inflammatory and proinflammatory lipid mediators could lead to the development of novel anti-inflammatory therapies for bronchiectasis.AimThe aim of our study was to characterise the lipids obtained from serum and airways in patients with bronchiectasis in the stable state.MethodsSix healthy volunteers, 10 patients with mild bronchiectasis, 15 with moderate bronchiectasis and 9 with severe bronchiectasis were recruited. All participants had 60 mL of blood taken and underwent a bronchoscopy while in the stable state. Lipidomics was done on serum and bronchoalveolar lavage fluid (BALF).ResultsIn the stable state, in serum there were significantly higher levels of prostaglandin E2 (PGE2), 15-hydroxyeicosatetranoic acid (15-HETE) and leukotriene B4 (LTB4) in patients with moderate–severe disease compared with healthy volunteers. There was a significantly lower level of lipoxin A4 (LXA4) in severe bronchiectasis.In BALF, there were significantly higher levels of PGE2, 5-HETE, 15-HETE, 9-hydroxyoctadecadienoic acid and LTB4 in moderate–severe patients compared with healthy volunteers.In the stable state, there was a negative correlation of PGE2 and LTB4 with % predicted forced expiratory volume in 1 s and a positive correlation with antibiotic courses.LXA4 improved blood and airway neutrophil phagocytosis and bacterial killing in patients with bronchiectasis. Additionally LXA4 reduced neutrophil activation and degranulation.ConclusionThere is a dysregulation of lipid mediators in bronchiectasis with excess proinflammatory lipids. LXA4 improves the function of reprogrammed neutrophils. The therapeutic efficacy of LXA4 in bronchiectasis warrants further studies.

Age-linked suppression of lipoxin A4 mediates cognitive deficits in mice and humans

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

Safety and Preliminary Efficacy of a Novel Host-Modulatory Therapy for Reducing Gingival Inflammation

BackgroundPeriodontal disease is among the sixth most common inflammatory diseases worldwide with high risk to promote complications from other inflammatory diseases including diabetes, cardiovascular disease and Alzheimer’s Disease. Failure of active resolution of inflammation pathways is implicated in pathogenesis of periodontal diseases, including gingivitis. Lipoxin A4 (LXA4), a member of the specialized pro-resolving lipid mediators (SPMs) that drive resolution of inflammation via GPC-receptor mediated pathways, offered therapeutic advantages in preclinical models of periodontitis.MethodsWe conducted a randomized, placebo-controlled, parallel-group Phase 1 clinical trial to determine the safety and preliminary efficacy of an LXA4 analog in patients with gingival inflammation. One hundred twenty-seven (127) individuals were randomized to daily use of an oral rinse containing a LXA4 mimetic, methyl ester-benzo-lipoxin A4 (BLXA4), placebo rinse or a no-rinse control group for 28 days. Treatment emergent adverse events (TEAEs) were assessed for safety, the primary outcome. Secondary outcomes included the change in the level of gingival inflammation and periodontal pocket depth (PD). Serum SPMs were monitored using targeted lipid mediator lipidomics to assess potential systemic impact of BLXA4.ResultsThe frequency of TEAEs was similar in BLXA4 and placebo-treated groups with no study-related SAEs. Once-daily rinsing with BLXA4 for 28-days resulted in a greater decrease in gingival inflammation compared to placebo rinse and no-rinse control groups (mean change: 0.26 GI unit vs 0.21 and 0.17, respectively). PD reduction was also greater with BLXA4 oral rinse compared to placebo and no-rinse groups (mean reduction: 1.23 mm vs. 0.71 mm and 0.46 mm, respectively). Topical application of BLXA4 increased serum levels of SPMs.ConclusionTreatment with BLXA4 reduces local inflammation, and increases abundance of pro-resolution molecules systemically, which may dampen inflammation that can mediate progression and course of inflammatory diseases beyond periodontitis.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT02342691).