Macrophage-derived lipid agonists of PPAR-<b>α</b>as intrinsic controllers of inflammation

Pontis, Silvia; Ribeiro, Alison; Sasso, Oscar; Piomelli, Daniele

doi:10.3109/10409238.2015.1092944

Cited by 64 publications

(51 citation statements)

References 71 publications

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“…In support of the present findings, previous reports have described the inhibitory effects of PPAR agonists on inflammatory mediators in vivo and vitro experiments (Libby et al 2007;Mutua et al 2015;Pontis et al 2016). In the present study, we measured the secretion of pro-inflammatory cytokines as the indicators for inflammatory response of synovial fibroblasts.…”

Section: Discussionsupporting

confidence: 92%

PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway

et al. 2016

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Osteoarthritis (OA), the most prevalent form of arthritis that results from breakdown of joint cartilage and underlying bone, has been viewed as a chronic condition manifested by persistence of inflammatory responses and infiltration of lymphocytes. Regulation of the inflammatory responses in synovial fibroblasts might be useful to prevent the development and deterioration of osteoarthritis. WY-14643, a potent peroxisome proliferator activator receptor-α (PPAR-α) agonist, has been described to beneficially regulate inflammation in many mammalian cells. Here, we investigate the potential anti-inflammatory role of WY-14643 in lipopolysaccharide (LPS)-induced synovial fibroblasts. WY-14643 greatly inhibited the production of NO and PGE2 induced by LPS. In addition, the mRNA expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), and tissue factor (TF) was significantly suppressed by WY-14643, as well as the secretion of pro-inflammatory cytokines including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1). Furthermore, the transcription activity and nuclear translocation of NF-kB were found to be markedly decreased by WY-14643, while the phosphorylation of IkB was enhanced, indicating that the anti-inflammatory role of WY-14643 was meditated by NF-kB-dependent pathway. The application of WY-14643 failed to carry out its anti-inflammatory function in PPAR-α silenced cells, suggesting the role of PPAR-α. These findings may facilitate further studies investigating the translation of pharmacological PPAR-α activation into clinical therapy of OA.

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Section: Discussionsupporting

confidence: 92%

PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway

et al. 2016

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“…These questions are likely to be interconnected. Previous studies have shown that two FAAH substrates present in the skin, PEA and OEA, modulate local inflammatory responses by activating the nuclear receptor PPAR-α (8,37). Like NAT formation after wounding, the production of PEA and OEA is suppressed by proinflammatory stimuli (38)(39)(40), suggesting that different classes of lipid amides may regulate distinct phases of the healing response in a coordinated manner.…”

Section: Discussionmentioning

confidence: 99%

“…In the skin, these lipid amides may act as local modulators of the homeostatic response to injury by regulating the activity of nociceptive terminals and resident immune cells (5)(6)(7). Partially overlapping functions may be served by the ethanolamides of saturated and monounsaturated fatty acids, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which also attenuate nociception and inflammation, but do so by binding to the ligand-operated transcription factor, peroxisome proliferator-activated receptor type-α (PPAR-α) (8). A third group of FAAH substrates, the amides of long-chain fatty acids with taurine [N-acyl-taurines (NATs)], has been identified in liver and other rodent tissues (9,10).…”

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confidence: 99%

Endogenous N -acyl taurines regulate skin wound healing

Sasso

Pontis

Armirotti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The intracellular serine amidase, fatty acid amide hydrolase (FAAH), degrades a heterogeneous family of lipid-derived bioactive molecules that include amides of long-chain fatty acids with taurine [N-acyl-taurines (NATs)]. The physiological functions of the NATs are unknown. Here we show that genetic or pharmacological disruption of FAAH activity accelerates skin wound healing in mice and stimulates motogenesis of human keratinocytes and differentiation of human fibroblasts in primary cultures. Using untargeted and targeted lipidomics strategies, we identify two longchain saturated NATs-N-tetracosanoyl-taurine [NAT(24:0)] and N-eicosanoyl-taurine [NAT(20:0)]-as primary substrates for FAAH in mouse skin, and show that the levels of these substances sharply decrease at the margins of a freshly inflicted wound to increase again as healing begins. Additionally, we demonstrate that local administration of synthetic NATs accelerates wound closure in mice and stimulates repair-associated responses in primary cultures of human keratinocytes and fibroblasts, through a mechanism that involves tyrosine phosphorylation of the epidermal growth factor receptor and an increase in intracellular calcium levels, under the permissive control of transient receptor potential vanilloid-1 receptors. The results point to FAAH-regulated NAT signaling as an unprecedented lipid-based mechanism of woundhealing control in mammalian skin, which might be targeted for chronic wound therapy.FAAH | N-acyl taurines | FAEs | fibroblasts | keratinocytes

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“…Pharmacological studies support this idea. Two main classes of potent NAAA inhibitors have been characterized so far (for review, see Pontis et al, 2015). The first is represented by b-lactone derivatives such as…”

Section: Discussionmentioning

confidence: 99%

An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

Bonezzi

Sasso

Pontis

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-a. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. Injection of CFA into the paw produced local edema and heat hyperalgesia, which were accompanied by decreased PEA and OEA content (assessed by liquid chromatography/mass spectrometry) and increased NAAA levels (assessed by Western blot and ex vivo enzyme activity measurements) in paw tissue. Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFAinduced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis.

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Macrophage-derived lipid agonists of PPAR-αas intrinsic controllers of inflammation

Cited by 64 publications

References 71 publications

PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway

PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway

Endogenous N -acyl taurines regulate skin wound healing

An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freunds Adjuvant Rat Model of Arthritis

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