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Aims: The cardio-protective and immuno-regulatory properties of RTP-026, a synthetic peptide that spans the Annexin-A1 (AnxA1) N-terminal region, were tested in rat acute myocardial infarction. Methods and results: In vitro, selective activation of formyl-peptide receptor type 2 (FPR2) by RTP-026 occurred with apparent EC50 in the 10–30 nM range. With human primary cells, RTP-026 counteracted extension of neutrophil life-span and augmented phagocytosis of fluorescent E.coli by blood myeloid cells. An in vivo model of rat acute infarction was used to quantify tissue injury and phenotype immune cells in myocardium and blood. The rat left anterior descending coronary artery was occluded and then reopened for 2-hour or 24-hour reperfusion. For the 2-hour reperfusion protocol, RTP-026 (25–500 µg/kg; given i.v. at the start of reperfusion) significantly reduced infarct size by ∼50 %, with maximal efficacy at 50 µg/kg. Analyses of cardiac immune cells showed that RTP-026 reduced neutrophil and classical monocyte recruitment to the damaged heart. In the blood, RTP-026 (50 µg/kg) attenuated activation of neutrophils and monocytes monitored through CD62L and CD54 expression. Modulation of vascular inflammation by RTP-026 was demonstrated by reduction in plasma levels of mediators like TNF-α, IL-1β, KC, PGE2 and PGF2α⊡ For the 24-hour reperfusion protocol, RTP-026 (30 µg/kg given i.v. at 0, 3 and 6 h reperfusion) reduced necrotic myocardium by ∼40 %. Conclusions: RTP-026 modulate immune cell responses and decreases infarct size of the heart in preclinical settings. Tempering over-exuberant immune cell activation by RTP-026 is a suitable approach to translate the biology of AnxA1 for therapeutic purposes.

Docosahexaenoic acid (DHA), a representative omega-3 (ω-3) polyunsaturated fatty acids, undergoes metabolism to produce biologically active electrophilic species. 17-Oxo-DHA is one such reactive metabolite generated from DHA by cyclooxygenase-2 and dehydrogenase in activated macrophages. The present study was aimed to investigate the effects of 17-oxo-DHA on ultraviolet B (UVB)-induced oxidative stress, inflammation, and carcinogenesis in mouse skin. UVB-induced epidermal cell death was ameliorated by topically applied 17-oxo-DHA. Topical application of 17-oxo-DHA onto hairless mouse skin inhibited UVB-induced phosphorylation of the proinflammatory transcription factor, STAT3 on tyrosine 705 (Tyr705). The 17-oxo-DHA treatment also reduced the levels of oxidative stress markers, 4-hydroxynonenal-modified protein, malondialdehyde, and 8-oxo-2′-deoxyguanosine. The protective effects of 17-oxo-DHA against oxidative damage in UVB-irradiated mouse skin were associated with activation of Nrf2. 17-Oxo-DHA enhanced the engulfment of apoptotic JB6 cells by macrophages, which was related to the increased expression of the scavenger receptor CD36. The 17-oxo-DHA-mediated potentiation of efferocytic activity of macrophages was attenuated by the pharmacologic inhibition or knockout of Nrf2. The pretreatment with 17-oxo-DHA reduced the UVB-induced skin carcinogenesis and tumor angiogenesis. It was also confirmed that 17-oxo-DHA treatment significantly inhibited the phosphorylation of the Tyr705 residue of STAT3 and decreased the expression of its target proteins in cutaneous papilloma. In conclusion, 17-oxo-DHA protects against UVB-induced oxidative cell death, dermatitis, and carcinogenesis. These effects were associated with inhibition of STAT3-mediated proinflammatory signaling and also activation of Nrf2 with subsequent upregulation of antioxidant and anti-inflammatory gene expression.

Objective: In this study, we tested the hypothesis that endogenous expression of specialized pro-resolving lipid mediators (SPMs) that facilitate the resolution of inflammation, specifically Resolvin D1and -D2, as well as Maresin1 (MaR1), can impact abdominal aortic aneurysm (AAA) formation and progression in a sex-specific manner. Methods: SPM expression was quantified in aortic tissue from human AAA samples and from a murine in vivo AAA model via liquid chromatography-tandem mass spectrometry. mRNA expression for SPM receptors FPR2, LGR6, and GPR18 were quantified by real-time polymerase chain reaction. A Student t test with nonparametric Mann-Whitney or Wilcoxon test was used for pair-wise comparisons of groups. One-way analysis of variance after post hoc Tukey test was used to determine the differences among multiple comparative groups. Results: Human aortic tissue analysis revealed a significant decrease in RvD1 levels in male AAAs compared with controls, whereas FPR2 and LGR6 receptor expressions were downregulated in male AAAs compared with male controls. In vivo studies of elastase-treated mice showed higher levels of RvD2 and MaR1 as well as the SPM precursors, omega-3 fatty acids DHA and EPA, in aortic tissue from males compared with females. FPR2 expression was increased in elastase-treated females compared with males. Conclusions: Our findings demonstrate that specific differences in SPMs and their associated G-protein coupled receptors exist between sexes. These results indicate the relevance of SPM-mediated signaling pathways in sex differences impacting the pathogenesis of AAAs. : Clinical Relevance: AAAs are a substantial clinical problem and can lead to sudden aortic rupture and death. Recent studies have shown a critical role for sex disparity during AAA formation, as female sex has a lower incidence of aortic aneurysm disease, but their outcomes following intervention appear to be worse. Few studies have examined the potential causes that underlie these differences. In this study, we tested the hypothesis that sex differences in endogenous SPM expression and their receptors exist between males and females and that this difference could be associated with AAA formation.

Aims: The cardio-protective and immuno-regulatory properties of RTP-026, a synthetic peptide that spans the Annexin-A1 (AnxA1) N-terminal region, were tested in rat acute myocardial infarction., Methods and Results: In vitro, selective activation of formyl-peptide receptor type 2 (FPR2) by RTP-026 occurred with apparent EC 50 in the 10-30 nM range. With human primary cells, RTP-026 counteracted extension of neutrophil life-span and augmented phagocytosis of fluorescent E.coli by blood myeloid cells. An in vivo model of rat acute infarction was used to quantify tissue injury and phenotype immune cells in myocardium and blood. The rat left anterior descending coronary artery was occluded and then reopened for 2-hour or 24-hour reperfusion. For the 2-hour reperfusion protocol, RTP-026 (25-500 µg/kg; given i.v. at the start of reperfusion) significantly reduced infarct size by ∼50 %, with maximal efficacy at 50 µg/kg. Analyses of cardiac immune cells showed that RTP-026 reduced neutrophil and classical monocyte recruitment to the damaged heart. In the blood, RTP-026 (50 µg/kg) attenuated activation of neutrophils and monocytes monitored through CD62L and CD54 expression. Modulation of vascular inflammation by RTP-026 was demonstrated by reduction in plasma levels of mediators like TNF-α, IL-1β, KC, PGE 2 and PGF 2α⊡ For the 24-hour reperfusion protocol, RTP-026 (30 µg/kg given i.v. at 0, 3 and 6 h reperfusion) reduced necrotic myocardium by ∼40 %., Conclusions: RTP-026 modulate immune cell responses and decreases infarct size of the heart in preclinical settings. Tempering over-exuberant immune cell activation by RTP-026 is a suitable approach to translate the biology of AnxA1 for therapeutic purposes., Competing Interests: Declaration of Competing Interest Mauro Perretti declares to be a shareholder of Antibe Therapeutics and ResoTher Pharma A/S and a director of William Harvey Research Limited; a scientific advisory board member for Antibe Therapeutics and SynAct Pharma Aps. Mauro Perretti and Jesmond Dalli are a co-inventor on a patent related to AnxA1 pro-resolving peptides (European Patent 3533457 B1). Thomas EN Jonassen is co-founder and shareholder of ResoTher Pharma A/S. Samra Sanni holds managerial position at ResoTher Pharma A/S. ResoTher Pharma A/S owns intellectual property rights on RTP-026., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Sleep disturbances, as manifested in insomnia symptoms of difficulties falling asleep or frequent nighttime awakenings, are a strong risk factor for a diverse range of diseases involving immunopathology. Low-grade systemic inflammation has been frequently found associated with sleep disturbances and may mechanistically contribute to increased disease risk. Effects of sleep disturbances on inflammation have been observed to be long lasting and remain after recovery sleep has been obtained, suggesting that sleep disturbances may not only affect inflammatory mediators, but also the so-called specialized pro-resolving mediators (SPMs) that actively resolve inflammation. The goal of this investigation was to test for the first time whether the omega-3 fatty acid-derived D- (RvD) and E-series (RvE) resolvins are impacted by prolonged experimental sleep disturbance (ESD)., Methods: Twenty-four healthy participants (12 F, age 20-42 years) underwent two 19-day in-hospital protocols (ESD/control), separated by > 2 months. The ESD protocol consisted of repeated nights of short and disrupted sleep with intermittent nights of undisturbed sleep, followed by three nights of recovery sleep at the end of the protocol. Under the control sleep condition, participants had an undisturbed sleep opportunity of 8 h/night throughout the protocol. The D- and E-series resolvins were measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: The precursor of the D-series resolvins, 17-HDHA, was downregulated in the ESD compared to the control sleep condition (p <.001 for condition), and this effect remained after the third night of recovery sleep has been obtained. This effect was also observed for the resolvins RvD3, RvD4, and RvD5 (p <.001 for condition), while RvD1 was higher in the ESD compared to the control sleep condition (p <.01 for condition) and RvD2 showed a mixed effect of a decrease during disturbed sleep followed by an increase during recovery sleep in the ESD condition (p <.001 for condition*day interaction). The precursor of E-series resolvins, 18-HEPE, was downregulated in the ESD compared to the control sleep condition (p <.01 for condition) and remained low after recovery sleep has been obtained. This effect of downregulation was also observed for RvE2 (p <.01 for condition), while there was no effect for RvE1 (p >.05 for condition or condition*day interaction). Sex-differential effects were found for two of the D-series resolvins, i.e., RvD2 and RvD4., Conclusion: This first investigation on the effects of experimental sleep disturbance on inflammatory resolution processes shows that SPMs, particularly resolvins of the D-series, are profoundly downregulated by sleep disturbances and remain downregulated after recovery sleep has been obtained, suggesting a longer lasting impact of sleep disturbances on these mediators. These findings also suggest that sleep disturbances contribute to the development and progression of a wide range of diseases characterized by immunopathology by interfering with processes that actively resolve inflammation. Pharmacological interventions aimed at promoting inflammatory resolution physiology may help to prevent future disease risk as a common consequence of sleep disturbances., Trial Registration: ClinicalTrials.gov NCT02484742., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The onset of labor is regulated by endocrine, nervous and immunological factors. This study was designed to determine the inflammatory and pro-resolving mediator levels in plasma and placenta of women undergoing labor induction in late-term pregnancy., Method: Healthy pregnant women admitted for delivery or labor induction were included. TNF, IL-1β, IL-6, IL-8, and IL-10 were quantified by ELISA in plasmatic and placental samples and Annexin A1 (ANXA1) in the placenta by Western Blotting, and immunofluorescence to CD15 + antibody. The data were analyzed using the Wilcoxon test and Spearman correlation. The p-value was significant when <0.05., Results: There was a higher concentration of IL-8 was found in the amniotic plaque (p = 0.042) and IL-10 (p < 0.001) in the trophoblast of patients with spontaneous labor. Greater ANXA1 density in the trophoblast was also observed in those with induction failure. There was a positive correlation of ANXA1 density in trophoblast induction duration with (r = 0.580) and with the IL-6 level in amniotic plaque (r = 0.517), and a positive correlation between labor duration and density of ANXA1 was identified in the trophoblast (r = 0.419). An increase was identified in CD15 + cell immunocapturing among the groups with spontaneous labor compared to the group with induction failure (p < 0.001)., Discussion: The inflammatory process in labor involves both maternal and fetal participation. Induction failure is associated with higher levels of ANXA1 in the trophoblast., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Inflammation and its timely resolution are critical to ensuring effective host defence and appropriate tissue repair after injury. Unresolved inflammation typifies many renal pathologies. The key drivers of the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. However, these are associated with undesirable side effects including immune suppression. More recently, there is growing appreciation that specialized lipid mediators [SPMs] including lipoxins promote the resolution of inflammation and endogenous repair mechanisms without compromising host defence. We discuss the pro-resolving bioactions of lipoxins and recent work that aims to harness their therapeutic potential in the context of kidney disease., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The resolution of inflammation is a dynamic process, characterized by the biosynthesis of pro-resolving mediators, including the lipid Lipoxin A4 (LXA 4 ). LXA 4 acts on the N-formyl peptide receptor 2 (FPR2/ALX) to mediate anti-inflammatory and pro-resolving effects. In order to exploit the therapeutic potential of endogenous LXA 4 in the context of inflammation we have recently developed synthetic LXA 4 mimetics (sLXms) including a dimethyl-imidazole-containing FPR2/ALX agonist designated AT-01-KG. Here, we have investigated the effect of treatment with AT-01-KG in established models of articular inflammation. In a model of gout, mice were injected with MSU crystals and treated with AT-01-KG at the peak of inflammatory response. The treatment decreased the number of neutrophils in the knee exudate, an effect which was accompanied by low levels of myeloperoxidase, CXCL1 and IL-1β in periarticular tissue. AT-01-KG treatment led to reduced tissue damage and hypernociception. The effects of AT-01-KG on neutrophil accumulation were not observed in MSU treated FPR2/3 -/- mice. Importantly, AT-01-KG induced resolution of articular inflammation by increasing neutrophil apoptosis and subsequent efficient efferocytosis. In a model of antigen-induced arthritis, AT-01-KG treatment also attenuated inflammatory responses. These data suggest that AT-01-KG may be a potential new therapy for neutrophilic inflammation of the joints., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Clinical effort in lipidology focuses largely on mitigating effects of atherosclerosis, a pathologic process localized to the intimal layer of larger arteries. This JCL Roundtable brings together 3 leading researchers to discuss the current understanding of pathogenesis in atherosclerosis. We begin by recognizing that low density lipoprotein concentrations in arterial intima far exceed concentrations in other connective tissues, consistent with the response-to-retention hypothesis of atherogenesis. High density lipoproteins facilitate reverse cholesterol transport and also have antioxidant and anti-inflammatory roles. New evidence points to remnants of triglyceride-rich lipoproteins as promoters of atherogenesis, highlighted by deleterious effects of apolipoprotein C-III. The multifaceted role of inflammation is becoming clearer through discoveries related to leukocyte recruitment, efferocytosis, resolution of inflammation, and crystal formation. MicroRNAs represent a new, complex mode of gene regulation bearing on lipoprotein and inflammation biology. Progress in understanding atherosclerosis portends a future in which residual risk related to obesity, diabetes, and other factors will yield to new targeted therapies., (Copyright © 2021. Published by Elsevier Inc.)

Aims: The present study aimed to evaluate the impact of chronic smoking and high fat diet on the post-MI metabolic features and inflammation resolution., Main Methods: Eight weeks old C57BL/6J mice were randomly divided into control(C), smoking(S), high-fat diet(H), and smoking plus high-fat diet(SH) groups for 16 weeks. MI was induced by permanent coronary ligation. Cardiac function was assessed by echocardiography at 5 days post-MI. The infarcted heart tissue was collected for the metabolic profile using metabolomics and quantification of pro-resolving mediators with immunoblotting., Key Findings: Percentage of fractional shortening (FS%) and ejection fraction (EF%) were further reduced in SH than that in either S or H group (P < 0.05). Myocardial metabolomics analysis indicated that 3, 6, and 11 disturbed metabolic pathways were considered as the most relevant pathway (Impact > 0.1) in S, H, and SH groups, respectively. The common most relevant pathway among three groups was arachidonic acid metabolism. The levels of arachidonic acid and TXB2 were significantly higher, while the 5-LOX and HO-1 expression was significantly lower in SH group than that in either S or H group (P < 0.05)., Significance: Smoking superimposed on high-fat diet could aggravate post-MI cardiac dysfunction and cause significant disturbance of metabolic pathways associated with inflammation, energy metabolism, as well as excessive oxidative stress. Smoking combined with high-fat diet could also magnify the post-MI inflammation and impair the resolution of inflammation in MI mice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Macrophages are professional phagocytes that display remarkable plasticity, with a range of phenotypes that can be broadly characterized by the M1/M2 dichotomy. Glucocorticoid (GC)-induced leucine zipper (GILZ) is a protein known to mediate anti-inflammatory and some pro-resolving actions, including as neutrophil apoptosis. However, the role of GILZ in key macrophage function is not well understood. Here, we investigated the role of GILZ on macrophage reprogramming and efferocytosis. Using murine bone-marrow-derived macrophages (BMDMs), we found that GILZ was expressed in naive BMDMs and exhibited increased expression in M2-like macrophages (IL4-differentiated). M1-like macrophages (IFN/LPS-differentiated) from GILZ -/- mice showed higher expression of the M1 markers CD86, MHC class II, iNOS, IL-6 and TNF-α, associated with increased levels of phosphorylated STAT1 and lower IL-10 levels, compared to M1-differentiated cells from WT mice. There were no changes in the M2 markers CD206 and arginase-1 in macrophages from GILZ -/- mice differentiated with IL-4, compared to cells from WT animals. Treatment of M1-like macrophages with TAT-GILZ, a cell-permeable GILZ fusion protein, decreased the levels of CD86 and MHC class II in M1-like macrophages without modifying CD206 levels in M2-like macrophages. In line with the in vitro data, increased numbers of M1-like macrophages were found into the pleural cavity of GILZ -/- mice after LPS-injection, compared to WT mice. Moreover, efferocytosis was defective in the context of GILZ deficiency, both in vitro and in vivo. Conversely, treatment of LPS-injected mice with TAT-GILZ promoted inflammation resolution, associated with lower numbers of M1-like macrophages and increased efferocytosis. Collectively, these data indicate that GILZ is a regulator of important macrophage functions, contributing to macrophage reprogramming and efferocytosis, both key steps for the resolution of inflammation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Asthma is characterized by inflammation, pulmonary remodeling and bronchial hyperresponsiveness. We have previously shown that treatment with angiotensin-(1-7) [Ang-(1-7)] promotes resolution of eosinophilic inflammation and prevents chronic allergic lung inflammation. Here, we evaluated the effect of treatment with the inclusion compound of Ang-(1-7) in hydroxypropyl β-cyclodextrin (HPβCD) given by inhalation on pulmonary remodeling in an ovalbumin (OVA)-induced chronic allergic lung inflammation. Mice were sensitized to ovalbumin (OVA; 4 injections over 42 days, 14 days apart) and were challenged 3 times per week, for 4 weeks (days 21-46). After the 2nd week of challenge, mice were treated with Ang-(1-7) by inhalation (4.5 μg of Ang-(1-7) included in 6.9 μg of HPβCD for 14 days, i.e. days 35-48). Mice were killed 72 h after the last challenge and blood, bronchoalveolar lavage fluid (BALF) and lungs were collected. Histology and morphometric analysis were performed in the lung. Metalloproteinase (MMP)-9 and MMP-12 expression and activity, IL-5, CCL11 in the lung and plasma IgE were measured. After 2 weeks of OVA challenge there was an increase in plasma IgE and in inflammatory cells infiltration in the lung of asthmatic mice. Treatment with inhaled administration of Ang-(1-7)/HPβCD for 14 days reduced eosinophils, IL5, CCL11 in the lung and plasma IgE. Treatment of asthmatic mice with Ang-(1-7)/HPβCD by inhalation reversed pulmonary remodeling by reducing collagen deposition and MMP-9 and MMP-12 expression and activity. These results show for the first time that treatment by inhalation with Ang-(1-7) can reverse an installed asthma, inhibiting pulmonary inflammation and remodeling., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Lifestyle or age-related risk factors over-activate the inflammation that triggers acute heart failure (HF)-related mortality following myocardial infarction (MI). Post-MI activated leukocytes express formyl peptide receptor 2 (FPR2) that is essential for inflammation-resolution and in cardiac healing. However, the role of FPR2 in acute HF is incomplete and remain of interest. Here, we aimed to determine whether pharmacological inhibition of FPR2 perturb leukocyte trafficking in acute HF. Male C57BL/6 (8-12 weeks) mice were subjected to acute HF (MI-d1) using permanent coronary artery ligation that develops irreversible acute and chronic heart failure. FPR2 antagonist WRW4 (1 μg/kg/day) was subcutaneously injected 3 h post-MI maintaining saline-injected MI-controls. Leukocytes were quantitated using flow cytometry, and acute decompensated HF was confirmed using echocardiography and histology. FPR2 inhibition decreased the expression of FPR2 in the LV and spleen tissues. Administration of WRW4 inhibitor to mice primed immature and inactive neutrophils infiltration Ly6G int and intensified the Ccl2 expression compared to MI-control in the infarcted LV post-MI. Leukocyte profiling revealed an overall decrease in monocytes (23.3 ± 2%) in WRW4-injected mice compared with MI-control (49.1 ± 2%) in infarcted LV. FPR2 inhibition increased F4/80 + /Ly6C hi pro-inflammatory macrophages (14.8 ± 2%) compared with MI-control (10 ± 1%) with increased transcripts of pro-inflammatory markers TNF-α and IL-1β, and decreased Arg-1 expression in the infarcted LV compared to MI-controls is suggestive of the impaired acute inflammatory response. Inhibition of FPR2 using WRW4 also disturbed splenocardiac leukocytes recruitment by priming immature neutrophils leading to the onset of incomplete resolution signaling in acute decompensated HF post-MI., (Published by Elsevier Ltd.)

Spinal cord injury (SCI) is an incurable disorder with an unmet need of an effective treatment. Recently, autologous human bone marrow-derived stem cells have shown to promote functional improvement, due to their anti-inflammatory and regenerative/apocrine properties. In this study, the primary objective was to test whether a single intrathecal injection with a 100 μL suspension of 400,000 fresh human bone marrow-derived CD34 + and an equal number of CD105 + stem cells (Neuro-Cells (NC)), one day after balloon-compression of the spinal cord, improves motor function and reduces secondary damage in immunodeficient rats. During the first 5 weeks after this intervention, NC significantly improved locomotor recovery and induced less injury-associated adverse events compared to vehicle-treated rats. Histological analysis showed that NC reduced astrogliosis, and apoptosis early after administration (day 4), but not at a later stage (day 56) after SCI. Proteomic studies (at day 56) pointed to the release of paracrine factors and identified proteins involved in regenerative processes. As stem cells seem to reach their effects in acute lesions by mainly suppressing (secondary) inflammation, it is thus realistic to expect a lower magnitude of their eventual beneficial effect in T-cell deficient rats, a fact reinforcing the robustness of Neuro-Cells efficacy. Taken together, this study indicates that an intrathecal instillation of Neuro-Cells holds great promise as a neuro-regenerative intervention in a clinical setting with acute SCI patients., (Copyright © 2019. Published by Elsevier B.V.)

Overstimulation of the pro-inflammatory pathways within brain areas responsible for sympathetic outflow is well evidenced as a primary contributing factor to the establishment and maintenance of neurogenic hypertension. However, the precise mechanisms and stimuli responsible for promoting a pro-inflammatory state are not fully elucidated. Recent work has unveiled novel compounds derived from omega-3 polyunsaturated fatty acids (ω-3 PUFAs), termed specialized pro-resolving mediators (SPMs), which actively regulate the resolution of inflammation. Failure or dysregulation of the resolution process has been linked to a variety of chronic inflammatory and neurodegenerative diseases. Given the pathologic role of neuroinflammation in the hypertensive state, SPMs and their associated pathways may provide a link between hypertension and the long-standing association of dietary ω-3 PUFAs with cardioprotection. Herein, we review recent progress in understanding the RAS-driven pathophysiology of neurogenic hypertension, particularly in regards to the chronic low-grade neuroinflammatory response. In addition, we examine the potential for an impaired resolution of inflammation process in the context of hypertension., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Phagocytosis of pathogens by macrophages is crucial for the successful resolution of inflammation induced by microbial infection. Taurine chloramine (TauCl), an endogenous anti-inflammatory and antioxidative substance, is produced by reaction between taurine and hypochlorous acid by myeloperoxidase activity in neutrophils under inflammatory conditions. In the present study, we investigated the effect of TauCl on resolution of acute inflammation caused by fungal infection using a zymosan A-induced murine peritonitis model. TauCl administration reduced the number of the total peritoneal leukocytes, while it increased the number of peritoneal monocytes. Furthermore, TauCl promoted clearance of pathogens remaining in the inflammatory environment by macrophages. When the macrophages isolated from thioglycollate-treated mice were treated with TauCl, their phagocytic capability was enhanced. In the murine macrophage-like RAW264.7 cells treated with TauCl, the proportion of macrophages clearing the zymosan A particles was also increased. TauCl administration resulted in elevated expression of heme oxygenase-1 (HO-1) in the peritoneal macrophages. Pharmacologic inhibition of HO-1 activity or knockdown of HO-1 in the murine macrophage RAW264.7 cells abolished the TauCl-induced phagocytosis, whereas the overexpression of HO-1 augmented the phagocytic ability of macrophages. Moreover, peritoneal macrophages isolated from HO-1 null mice failed to mediate TauCl-induced phagocytosis. Our results suggest that TauCl potentiates phagocytic activity of macrophages through upregulation of HO-1 expression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lipoxin A4 (LXA 4 ) is a metabolic product of arachidonic acid. Despite potent anti-inflammatory and pro-resolution activities, it remains to be determined if LXA 4 has effect on ultraviolet (UV) radiation-induced skin inflammation., Objective: To investigate the effects of systemic administration with LXA 4 on UV radiation-induced inflammation and oxidative damage in the skin of mice., Methods: Varied parameters of inflammation and oxidative stress in the skin of mice were evaluated after UV radiation (4.14 J/cm 2 )., Results: Pretreatment with LXA 4 significantly inhibited UV radiation-induced skin edema and myeloperoxidase activity. LXA 4 efficacy was enhanced by increasing the time of pre-treatment to up to 72 h. LXA 4 reduced UV radiation-induced skin edema, neutrophil recruitment (myeloperoxidase activity and LysM-eGFP + cells), MMP-9 activity, deposition of collagen fibers, epidermal thickness, sunburn cell counts, and production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-33). Depending on the time point, LXA 4 increased the levels of anti-inflammatory cytokines (TGF-β and IL-10). LXA 4 significantly attenuated UV radiation-induced oxidative damage returning the oxidative status to baseline levels in parameters such as ferric reducing ability, scavenging of free radicals, GSH levels, catalase activity and superoxide anion production. LXA 4 also reduced UV radiation-induced gp91 phox [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) subunit] mRNA expression and enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target enzyme nicotinamide adenine dinucleotide (phosphate) quinone oxidoreductase (Nqo1) mRNA expression., Conclusion: LXA 4 inhibited UV radiation-induced skin inflammation by diminishing pro-inflammatory cytokine production and oxidative stress as well as inducing anti-inflammatory cytokines and Nrf2., (Copyright © 2018. Published by Elsevier B.V.)

Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, are persistent disorders that lead to development of colitis-associated cancer (CAC). Facilitated resolution of colitis has been addressed as a novel therapeutic strategy to control development of CAC. Resolvin D1 (RvD1) is an endogenous lipid mediator that is generated from docosahexaenoic acid during the resolution of inflammation. Although the pro-resolving effects of RvDs have been extensively investigated and well defined, the role for RvD1 in CAC remains largely unknown. In this study, we found that RvD1 inhibited the expression of c-Myc in normal colon cells stimulated with tumor necrosis factor-α (TNFα) and also in colon cancer cells. The suppression of TNFα-induced upregulation of c-Myc in normal cells was mediated through attenuation of NF-κB signaling. Notably, RvD1 destabilized the constitutively overexpressed c-Myc protein in HCT 116 human colon cancer cells by stimulating its ubiquitination and subsequent proteasomal degradation. Further, we revealed that RvD1 stimulated c-Myc degradation through direct interaction with the ALX/FPR2 receptor. This interaction resulted in inhibition of activation of extracellular signal-regulated kinase, thereby attenuating phosphorylation-dependent stabilization of c-Myc., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Oral supplementation with n-3 polyunsaturated fatty acids (PUFA) increases the omega-3 index, a biomarker of red blood cell eicosapentaenoic acid and docosahexaenoic acid, and plasma levels of biosynthesis pathway markers and potent lipid mediators involved in the resolution of inflammation among patients with peripheral arterial disease (PAD)., Objective: We aimed to quantify the association between an upstream change in the omega-3 index and downstream changes in lipid mediator production., Methods: We conducted a secondary analysis of the OMEGA-PAD I Trial, a randomized, placebo controlled trial investigating high-dose n-3 PUFA oral supplementation in PAD patients. Eighty subjects were randomized to either 4.4 g of fish oil or placebo for 1 month. Regression analyses using generalized estimating equation techniques were used to investigate the relationship between changes in the omega-3 index and changes in lipid mediators, pre- and post-intervention., Results: In the fish oil group, there was a significant increase in the omega-3 index (5 ± 1% to 9 ± 2%, P < .001) as well as in the plasma levels of several downstream lipid mediator pathway markers of resolution, which are involved with the regulation of leukocyte effector function and host defense. A doubling of the omega-3 index correlated with increases of 2.3-fold in 18-hydroxy-eicosapentaenoic acid (HEPE; P < .0001), 1.7-fold in 15-HEPE (P = .03), 1.9-fold in 5-HEPE (P = .04), and 3.6-fold in 4-hydroxy-docosahexaenoic acid (P < .001)., Conclusion: Among subjects with symptomatic PAD who took oral fish oil supplements for 1 month, observed changes in the omega-3 index were strongly associated with increases in downstream mediators in the biochemical pathways of resolution., (Copyright © 2017 National Lipid Association. All rights reserved.)

Alzheimer disease (AD) is becoming one of the most prevalent neurodegenerative conditions worldwide. Although the disease progression is becoming better understood, current medical interventions can only ameliorate some of the symptoms but cannot slow disease progression. Neuroinflammation plays an important role in the advancement of this disorder, and n-3 (ω-3) polyunsaturated fatty acids (PUFAs) are involved in both the reduction in and resolution of inflammation. These effects may be mediated by the anti-inflammatory and proresolving effects of bioactive lipid mediators (oxylipins) derived from n-3 PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in fish oil. Although interventions have generally used fish oil containing both EPA and DHA, several studies that used either EPA or DHA alone or specific oxylipins derived from these fatty acids indicate that they have distinct effects. Both DHA and EPA can reduce neuroinflammation and cognitive decline, but EPA positively influences mood disorders, whereas DHA maintains normal brain structure. Fewer studies with a plant-derived n-3 PUFA, α-linolenic acid, suggest that other n-3 PUFAs and their oxylipins also may positively affect AD. Further research identifying the unique anti-inflammatory and proresolving properties of oxylipins from individual n-3 PUFAs will enable the discovery of novel disease-management strategies in AD., Competing Interests: 2 Author disclosures: JG Devassy, S Leng, M Gabbs, M Monirujjaman, and HM Aukema, no conflicts of interest., (© 2016 American Society for Nutrition.)

Aims: Impaired resolution of acute inflammation results in development of chronic inflammatory disorders such as atherosclerosis, asthma and arthritis. Clearance of apoptotic neutrophils by M2 macrophages, the process termed efferocytosis, is critical for complete resolution of inflammation as it prevents secondary necrosis caused by disgorgement of toxic contents from apoptotic cells in the inflamed site. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on efferocytosis., Main Methods: To determine the effect of DHA on efferocytosis, murine macrophage-like RAW264.7 cells were co-incubated with apoptotic Jurkat T cells, and efferocytosis was assessed by flow cytometry. The expression and production of M1 and M2 markers were determined by RT-PCR, ELISA and flow cytometry. To demonstrate the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in DHA-mediated effects, siRNA against PPARγ was utilized. The expression of PPARγ was examined by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot analysis and immunocytochemistry. The PPARγ activation was measured by the electrophilic gel shift assay., Key Findings: DHA enhanced the efferocytic ability of RAW264.7 cells, and induced their M2 polarization. Notably, knockdown of PPARγ abolished the stimulatory effect of DHA on M2 polarization as well as efferocytosis. Furthermore, lipopolysaccharide-induced production of pro-inflammatory cytokines was significantly inhibited by DHA, suggesting that DHA alters the macrophage phenotype in favor of M2 while it suppresses M1 polarization., Significance: These findings indicate that DHA can promote resolution of inflammation by facilitating efferocytosis through M2 macrophage polarization. Therefore, DHA may have a therapeutic potential in the management of inflammatory diseases which are related to impaired resolution of inflammation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Murine zymosan-induced peritonitis is the model most frequently used to study resolution of inflammation. However, the antigen-induced peritonitis model may be better suited for studying resolution of inflammation and the adaptive phase that follows. The objective of this study was to provide an evaluation of the kinetics of cells and mediators during induction, resolution and the adaptive immune phases of a murine antigen-induced inflammation. Female C57BL/6 mice were immunized twice subcutaneously with mBSA and three weeks after the initial immunization they were injected intraperitoneally (i.p.) with mBSA, which induced peritonitis. Peritoneal cells were counted and expression of surface molecules and chemokine receptors analyzed with flow cytometry. Chemokine and cytokine concentrations in peritoneal fluid were determined by ELISA. Two neutrophil populations, differing in size and granularity and slightly in expression of surface molecules, were observed in the peritoneal cavity after induction of inflammation. Macrophages disappeared from the peritoneal cavity following i.p. administration of mBSA but appeared again as they differentiated from recruited monocytes and peaked in numbers at 48 h. At that time point, two distinct populations of macrophages were present in the peritoneal cavity; one with high expression of F4/80, also expressing the atypical chemokine receptor D6 as well as CCR7; the other expressing low levels of F4/80 and also expressing CD11c and CD138. Eosinophils appeared in the peritoneum 3h following i.p. administration of mBSA and peaked at 48 h. At that time point they had upregulated their expression of CCR3 but decreased their expression of CD11b. Peritoneal levels of CCL11 peaked at 6h and may have led to recruitment of the eosinophils. NK cells and T cells peaked at 48 h, whereas B cells peaked at 5 days, with the majority being B1 cells. Peritoneal concentrations of pro-inflammatory cytokines (IL-β and IL-6) and chemokines (CCL2 and CCL3) peaked at 3h, whereas IL-1ra peaked at 6h, sTNF-R at 24h and sIL-6R and TGF-β at 48 h. The results show kinetic alterations in cell populations and mediators in a murine model that may be an excellent model to study initiation and resolution of inflammation and the following adaptive phase., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Macrophages, and more broadly inflammation, have been considered for a long time as bad markers of tissue homeostasis. However, if it is indisputable that macrophages are associated with many diseases in a deleterious way, new roles have emerged, showing beneficial properties of macrophages during tissue repair and regeneration. This discrepancy is likely due to the high plasticity of macrophages, which may exhibit a wide range of phenotypes and functions depending on their environment. Therefore, regardless of their role in immunity, macrophages play a myriad of roles in the maintenance and recovery of tissue homeostasis. They take a major part in the resolution of inflammation. They also exert various effects of parenchymal cells, including stem and progenitor cell, of which they regulate the fate. In the present review, few examples from various tissues are presented to illustrate that, beyond their specific properties in a given tissue, common features have been described that sustain a role of macrophages in the recovery and maintenance of tissue homeostasis., (Copyright © 2013 Elsevier GmbH. All rights reserved.)