Proinflammatory Stimuli Control<i>N</i>-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

Zhu, Chenggang; Solórzano, Carlos Ortiz de; Sahar, Saurabh; Realini, Natalia; Fung, Ernest S.; Sassone–Corsi, Paolo; Piomelli, Daniele

doi:10.1124/mol.110.070201

Cited by 78 publications

(77 citation statements)

References 38 publications

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“…6A, CFA injection was accompanied by an increase in NAAA in inflamed paws, as assessed by activity assays, and this effect was significantly reduced by administration of ARN726 (30 mg/kg, i.p.). ARN726 also normalized paw levels of PEA and OEA, which, as expected from previous work (Zhu et al, 2011;Sasso et al, 2013;Ribeiro et al, 2015), were lowered by treatment with CFA (Fig. 6, B and C).…”

Section: Resultssupporting

confidence: 68%

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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Section: Resultssupporting

confidence: 68%

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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“…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. Answering these questions may help uncover possible roles of NAT-mediated signaling in pathological impairments of skin repair, such as those consequent to aging, diabetes, and immunosuppression, and might guide the development of new strategies for the management of chronic nonresolving wounds.…”

Section: Discussionmentioning

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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“…Processing of NAAA renders a cysteine residue (Cys131 in mice and rats and Cys126 in humans) the N-terminal amino acid and catalytic nucleophile. 18,21,22 Pharmacological blockade of intracellular NAAA activity results in a normalization of OEA and PEA levels, which are markedly reduced in inflammatory states, 18,23,24 and exerts profound anti-inflammatory effects in animal models. 18 These findings suggest that NAAA inhibition might represent a novel mechanistic approach to control inflammation.…”

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confidence: 99%

β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

Armirotti

Romeo

Ponzano

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:The cysteine amidase N-acylethanolamine acid amidase (NAAA) is a member of the N-terminal nucleophile class of enzymes and a potential target for anti-inflammatory drugs. We investigated the mechanism of inhibition of human NAAA by substituted β-lactones. We characterized pharmacologically a representative member of this class, ARN077, and showed, using high-resolution liquid chromatography−tandem mass spectrometry, that this compound forms a thioester bond with the N-terminal catalytic cysteine in human NAAA. KEYWORDS: NAAA, cysteine amidase, covalent inhibitors, high resolution mass spectrometry, proteomics T he fatty acid ethanolamides (FAEs) are a family of bioactive lipid molecules that have attracted considerable interest due to their potential role in the control of pain, inflammation, and energy metabolism. Two structurally and functionally distinct classes of FAEs have been described. Polyunsaturated FAEs, such as arachidonoylethanolamide (anandamide) and eicosapentaenoylethanolamide, are endogenous agonists of G protein-coupled cannabinoid receptors. 1,2 These compounds are thought to act as retrograde messengers at synapses of the central nervous system and as local mediators in peripheral tissues. In the brain, anandamide-mediated signaling at CB 1 type cannabinoid receptors has been implicated in the regulation of anxiety, 3 depression, 4,5 stress-induced analgesia, 6 and nausea. 7 Outside the brain, anandamide released at sites of tissue injury is thought to control the initiation of emerging pain signals, 8,9 presumably by reducing the local release of proalgesic and proinflammatory factors from nociceptive nerve terminals. 10 The biological actions of anandamide are interrupted by a two-step deactivation process consisting of carriermediated transport into cells 11,12 followed by intracellular hydrolysis, which is catalyzed by the membrane-bound serine hydrolase, fatty acid amide hydrolase (FAAH). Inhibitors of this enzyme protect anandamide from deactivation and selectively magnify its intrinsic actions, producing an array of pharmacological effects that include reduced anxiety, depression, and pain. 13 Saturated and monounsaturated FAEs, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), do not productively interact with cannabinoid receptors. These compounds are, however, potent or moderately potent agonists of nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is responsible for most of their analgesic and anti-inflammatory properties. 14−16 OEA and PEA are produced in many mammalian tissues, including neurons 17 and innate immune cells, 18 where a selective phospholipase D releases them by cleaving the membrane precursor, N-acyl-phosphatidylethanolamine. 19 They are deactivated either by FAAH, which prefers anandamide and OEA over PEA, or by NAAA, which conversely prefers PEA and OEA over anandamide. 20 Despite its functional similarity with FAAH, NAAA shares no homology with this or other enzymes of the same "amidase signature" family. Rather,...

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Proinflammatory Stimuli ControlN-Acylphosphatidylethanolamine-Specific Phospholipase D Expression in Macrophages

Cited by 78 publications

References 38 publications

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

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

Endogenous N -acyl taurines regulate skin wound healing

β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

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