Therapeutic potential of the FPR2/ALX agonist AT-01-KG in the resolution of articular inflammation

Galvão, Izabela; Melo, Eliza Mathias; Oliveira, Vívian Louise Soares de; Vago, Juliana P.; Queiroz-Júnior, Celso Martins; Gaetano, Monica de; Brennan, Eoin; Gahan, Kevin; Guiry, Patrick J.; Godson, Catherine; Teixeira, Mauro Martins

doi:10.1016/j.phrs.2021.105445

Cited by 21 publications

(17 citation statements)

References 52 publications

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“…The replacement of the triene core of LXA 4 with a benzene ring has led to the generation of several aromatic mimetics 153 that are protective in experimental models of diabetes-associated kidney disease and atherosclerosis, with evidence that these mimetics can halt and even reverse established disease 129,154 . Building on these findings, several synthetic imidazole and oxazole-containing lipoxin mimics have demonstrated potent effects in mouse models of peritonitis and arthritis 147,155 . Other synthetic agonists of ALX/FPR2 have shown efficacy in myocardial IRI 156,157 , and in preventing the development…”

Section: Resolution Pharmacologymentioning

confidence: 99%

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

et al. 2021

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Section: Resolution Pharmacologymentioning

confidence: 99%

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

et al. 2021

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“…In accordance, lipoxin A4 (LXA 4 ) exploits the N-formyl peptide receptor 2 (FPR2) for the efferocytosis and diminishes the release of pro-inflammatory cytokines leading to the resolution of inflammation. Galvao et al recently found a synthetic LXA 4 mimetic with ALX/FPR2 agonist nature, AT-01-KG to enhance the resolution of neutrophilic inflammation in monosodium urate-induced gout and antigeninduced murine arthritis model [98]. The treatment of this dimethyl-imidazole AT-01-KG led to an increase in apoptosis and further efferocytosis of neutrophils [98].…”

Section: Cellular Uptake and Receptorsmentioning

confidence: 99%

“…Galvao et al recently found a synthetic LXA 4 mimetic with ALX/FPR2 agonist nature, AT-01-KG to enhance the resolution of neutrophilic inflammation in monosodium urate-induced gout and antigeninduced murine arthritis model [98]. The treatment of this dimethyl-imidazole AT-01-KG led to an increase in apoptosis and further efferocytosis of neutrophils [98]. Though these recent studies have started to put light on lytic death remnants induced inflammatory consequences, specific involvement of receptors/pathways and their discrimination from apoptotic death clearance require further investigations.…”

Section: Cellular Uptake and Receptorsmentioning

confidence: 99%

Neutrophil and remnant clearance in immunity and inflammation

Singhal

Kumar

2021

Immunology

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Neutrophil-centred inflammation and flawed clearance of neutrophils cause and exuberate multiple pathological conditions. These most abundant leukocytes exhibit very high daily turnover in steady-state and stress conditions. Various armours including oxidative burst, NETs and proteases function against pathogens, but also dispose neutrophils to spawn pro-inflammatory responses. Neutrophils undergo death through different pathways upon ageing, infection, executing the intruder's elimination. These include non-lytic apoptosis and other lytic deaths including NETosis, necroptosis and pyroptosis with distinct disintegration of the cellular membrane. This causes release and presence of different intracellular cytotoxic, and tissue-damaging content as cell remnants in the extracellular environment. The apoptotic cells and apoptotic bodies get cleared with non-inflammatory outcomes, while lytic deaths associated remnants including histones and cell-free DNA cause pro-inflammatory responses. Indeed, the enhanced frequencies of neutrophil-associated proteases, cell-free DNA and autoantibodies in diverse pathologies including sepsis, asthma, lupus and rheumatoid arthritis, imply disturbed neutrophil resolution programmes

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“…Simiaowan reduced neutrophil infiltration, inhibited endothelial cell apoptosis in rats with MSU-induced gout, and improved the inflammatory response by attenuating the expression of ICAM-1 ( 148 ). AT-01-KG, an artificial agonist of FRP2/ALX, inhibits inflammation by inducing neutrophil apoptosis and cytarabine in a mouse model of gouty arthritis ( 94 ). Natural traditional medicines have also been shown to inhibit apoptosis of chondrocytes in gouty arthritis, as summarized in a previous review ( 153 ).…”

Section: Apoptosismentioning

confidence: 99%

Inflammatory Response to Regulated Cell Death in Gout and Its Functional Implications

et al. 2022

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Gout, a chronic inflammatory arthritis disease, is characterized by hyperuricemia and caused by interactions between genetic, epigenetic, and metabolic factors. Acute gout symptoms are triggered by the inflammatory response to monosodium urate crystals, which is mediated by the innate immune system and immune cells (e.g., macrophages and neutrophils), the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pro-inflammatory cytokine (e.g., IL-1β) release. Recent studies have indicated that the multiple programmed cell death pathways involved in the inflammatory response include pyroptosis, NETosis, necroptosis, and apoptosis, which initiate inflammatory reactions. In this review, we explore the correlation and interactions among these factors and their roles in the pathogenesis of gout to provide future research directions and possibilities for identifying potential novel therapeutic targets and enhancing our understanding of gout pathogenesis.

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Therapeutic potential of the FPR2/ALX agonist AT-01-KG in the resolution of articular inflammation

Cited by 21 publications

References 52 publications

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

Neutrophil and remnant clearance in immunity and inflammation

Inflammatory Response to Regulated Cell Death in Gout and Its Functional Implications

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