Impact of colonic mucosal lipoxin A4 synthesis capacity on healing in rats with dextran sodium sulfate-induced colitis

Ağış, Erol Rauf; Savaş, Berna; Melli, Mehmet

doi:10.1016/j.prostaglandins.2015.04.001

Cited by 16 publications

(6 citation statements)

References 33 publications

(63 reference statements)

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“…Similarly, IL-6 significantly increased ChemR23 expression in human monocytes and DCs over time ( Fig. 2A ) as previously described ( 32 , 45 – 47 ). In naïve mice, ChemR23 expression at steady state in the spleen was significantly lower than in resident macrophages and DCs in the colon (fig.…”

Section: Resultssupporting

confidence: 87%

“…RvE1, an endogenous lipid that binds to and activates ChemR23 receptor, has been shown to promote resolutive macrophage polarization, inhibit neutrophil recruitment, induce neutrophil apoptosis, and promote efferocytosis in resolutive-type macrophages ( 32 , 37 , 46 , 69 ). We have identified an anti-human ChemR23 mAb with similar receptor signaling functions as RvE1, including in promoting macrophage resolutive polarization as well as inflammatory neutrophil migration and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…SPM production is reduced in the colonic mucosa of patients with UC (29), and conversely, increased expression of SPMs in UC colon tissue is associated with remission and mucosa homeostasis (27,28). Notably, it has been shown that exogenous treatment with resolvin E1 (RvE1) accelerates the resolution of colon inflammation in acute, spontaneously resolutive colitis mouse models (32)(33)(34). RvE1 triggers extracellular signal-regulated kinase (ERK) and Akt signaling via activation of ChemR23 GPCRs (CMKLR1 gene) expressed by myeloid cells such as macrophages, dendritic cells (DCs), neutrophils, and natural killer (NK) cells (35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

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Agonist anti-ChemR23 mAb reduces tissue neutrophil accumulation and triggers chronic inflammation resolution

et al. 2021

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Resolution of inflammation is elicited by proresolving lipids, which activate GPCRs to induce neutrophil apoptosis, reduce neutrophil tissue recruitment, and promote macrophage efferocytosis. Transcriptional analyses in up to 300 patients with Inflammatory Bowel Disease (IBD) identified potential therapeutic targets mediating chronic inflammation. We found that ChemR23, a GPCR targeted by resolvin E1, is overexpressed in inflamed colon tissues of severe IBD patients unresponsive to anti-TNFα or anti-α4β7 therapies and associated with significant mucosal neutrophil accumulation. We also identified an anti-ChemR23 agonist antibody that induces receptor signaling, promotes macrophage efferocytosis, and reduces neutrophil apoptosis at the site of inflammation. This ChemR23 mAb accelerated acute inflammation resolution and triggered resolution in ongoing chronic colitis models, with a significant decrease in tissue lesions, fibrosis and inflammation-driven tumors. Our findings suggest that failure of current IBD therapies may be associated with neutrophil infiltration and that ChemR23 is a promising therapeutic target for chronic inflammation.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Agonist anti-ChemR23 mAb reduces tissue neutrophil accumulation and triggers chronic inflammation resolution

et al. 2021

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“…Impaired LX biosynthesis was found in colonic mucosa from UC patients while lipoxin A4 (LXA4) levels were increased in the mucosa of those in disease remission, along with increased macrophage infiltration and increased mRNA of LXA4 receptor formyl peptide receptor 2 (FPR2/ALX) [213,215]. LXA4 levels were also found to be negatively correlated with histopathologic alterations in experimental colitis, suggesting a beneficial role for this SPM in IBD [216]. NPD1 levels were increased in the colon of mice with dextran sulfate sodium (DSS)-induced colitis and decreased in colonic tissue of eosinophildeficient mice that develop more severe acute colitis compared to control mice [209,212].…”

Section: Gi Autoimmune Diseasesmentioning

confidence: 99%

Lipidomics in Understanding Pathophysiology and Pharmacologic Effects in Inflammatory Diseases: Considerations for Drug Development

et al. 2022

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The lipidome has a broad range of biological and signaling functions, including serving as a structural scaffold for membranes and initiating and resolving inflammation. To investigate the biological activity of phospholipids and their bioactive metabolites, precise analytical techniques are necessary to identify specific lipids and quantify their levels. Simultaneous quantification of a set of lipids can be achieved using high sensitivity mass spectrometry (MS) techniques, whose technological advancements have significantly improved over the last decade. This has unlocked the power of metabolomics/lipidomics allowing the dynamic characterization of metabolic systems. Lipidomics is a subset of metabolomics for multianalyte identification and quantification of endogenous lipids and their metabolites. Lipidomics-based technology has the potential to drive novel biomarker discovery and therapeutic development programs; however, appropriate standards have not been established for the field. Standardization would improve lipidomic analyses and accelerate the development of innovative therapies. This review aims to summarize considerations for lipidomic study designs including instrumentation, sample stabilization, data validation, and data analysis. In addition, this review highlights how lipidomics can be applied to biomarker discovery and drug mechanism dissection in various inflammatory diseases including cardiovascular disease, neurodegeneration, lung disease, and autoimmune disease.

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“…In IBD, a lower level of LXA4 has been reported in the colic mucosa of patients suffering from UC while remission was associated with a higher expression of LX4 and ALX receptors ( 193 , 194 ). In a dextran sodium sulfate (DSS)-induced colitis in rats the increase in LXA4 after misoprostol therapy was associated with reduced severity score during both acute and healing phases ( 195 ). Mar1, as well as PD1n-3 DPA and RvD5n-3 DPA, were reported to exert a protective effect in DSS-induced colitis and improved by aspirin treatment through its AT-LXs and AT-RvDs derivatives ( 175 , 196 – 198 ).…”

Section: Specialized Pro-resolving Lipid Mediatorsmentioning

confidence: 99%

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

et al. 2022

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Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.

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Impact of colonic mucosal lipoxin A4 synthesis capacity on healing in rats with dextran sodium sulfate-induced colitis

Cited by 16 publications

References 33 publications

Agonist anti-ChemR23 mAb reduces tissue neutrophil accumulation and triggers chronic inflammation resolution

Agonist anti-ChemR23 mAb reduces tissue neutrophil accumulation and triggers chronic inflammation resolution

Lipidomics in Understanding Pathophysiology and Pharmacologic Effects in Inflammatory Diseases: Considerations for Drug Development

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

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