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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2014

Open Access 01-12-2014 | Research

Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 by macrophages and increases the resistance of mice against infections

Authors: Sandra Redlich, Sandra Ribes, Sandra Schütze, Roland Nau

Published in: Journal of Neuroinflammation | Issue 1/2014

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Abstract

Background

Palmitoylethanolamide (PEA), an endogenous lipid and a congener of anandamide, possesses a wide range of effects related to metabolic and cellular homeostasis including anti-inflammatory and neuroprotective properties.

Methods

In vitro, we studied the ability of macrophages to phagocytose Escherichia coli K1 after stimulation with increasing doses of PEA. In vivo, wild-type mice were treated with PEA intraperitoneally 12 hours and 30 minutes before infection. Meningoencephalitis or sepsis was induced by intracerebral or intraperitoneal infection with E. coli K1.

Results

Stimulation of macrophages with PEA for 30 minutes increased the phagocytosis of E. coli K1 without inducing the release of TNFα or CXCL1. Intracellular killing of E. coli K1 was higher in PEA-stimulated than in unstimulated peritoneal macrophages and microglial cells. Pre-treatment with PEA significantly increased survival of mice challenged intracerebrally or intraperitoneally with E. coli K1. This effect was associated with a decreased production of CXCL1, IL-1β and IL-6 in homogenates of spleen and cerebellum in mice treated with PEA.

Conclusions

Our observations suggest that these protective effects of PEA in mice can increase the resistance to bacterial infections without the hazard of collateral damage by excessive stimulation of phagocytes.
Appendix
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Literature
1.
Petrosino S, Iuvone T, Di Marzo V: N-palmitoyl-ethanolamine: biochemistry and new therapeutic opportunities. Biochimie. 2010, 92: 724-727.CrossRefPubMed
2.
Coburn AF, Graham CE, Hahinger J: Effect of egg yolk in diets on anaphylactic arthritis (passive Arthus phenomenon) in the guinea pig. J Exp Med. 1954, 100: 425-435.PubMedCentralCrossRefPubMed
3.
Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A: N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by downmodulating mast cell activation. Eur J Pharmacol. 1996, 300: 227-236.CrossRefPubMed
4.
Calignano A, La RG, Giuffrida A, Piomelli D: Control of pain initiation by endogenous cannabinoids. Nature. 1998, 394: 277-281.CrossRefPubMed
5.
Lambert DM, Vandevoorde S, Diependaele G, Govaerts SJ, Robert AR: Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice. Epilepsia. 2001, 42: 321-327.CrossRefPubMed
6.
Esposito E, Cuzzocrea S: Palmitoylethanolamide in homeostatic and traumatic central nervous system injuries. CNS Neurol Disord Drug Targets. 2013, 12: 55-61.CrossRefPubMed
7.
Esposito E, Impellizzeri D, Mazzon E, Paterniti I, Cuzzocrea S: Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson’s disease. PLoS One. 2012, 7: e41880.PubMedCentralCrossRefPubMed
8.
Scuderi C, Steardo L: Neuroglial roots of neurodegenerative diseases: therapeutic potential of palmitoylethanolamide in models of Alzheimer’s disease. CNS Neurol Disord Drug Targets. 2013, 12: 62-69.CrossRefPubMed
9.
Facci L, Dal TR, Romanello S, Buriani A, Skaper SD, Leon A: Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A. 1995, 92: 3376-3380.PubMedCentralCrossRefPubMed
10.
Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G: Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol. 2002, 135: 181-187.PubMedCentralCrossRefPubMed
11.
Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D: The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol. 2005, 67: 15-19.CrossRefPubMed
12.
LoVerme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, Meli R, Hohmann A, Calignano A, Piomelli D: Rapid broadspectrum analgesia through activation of peroxisome proliferatoractivated receptor-alpha. J. Pharmacol Exp Ther. 2006, 319: 1051-1061.CrossRefPubMed
13.
Carroll CB, Zeissler ML, Chadborn N, Gibson K, Williams G, Zajicek JP, Morrison KE, Hanemann CO: Changes in iron-regulatory gene expression occur in human cell culture models of Parkinson’s disease. Neurochem Int. 2011, 59: 73-80.CrossRefPubMed
14.
De Petrocellis L, Davis JB, Di Marzo V: Palmitoylethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett. 2001, 506: 253-256.CrossRefPubMed
15.
Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ: The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007, 152: 1092-1101.PubMedCentralCrossRefPubMed
16.
17.
Stella N, Piomelli D: Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur J Pharmacol. 2001, 425: 189-196.CrossRefPubMed
18.
Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N: Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci. 2003, 23: 7767-7775.PubMed
19.
Redlich S, Ribes S, Schutze S, Czesnik D, Nau R: Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 and Streptococcus pneumoniae R6 by microglial cells. J Neuroimmunol. 2012, 244: 32-34.CrossRefPubMed
20.
Nau R, Eiffert H: Modulation of release of proinflammatory bacterial compounds by antibacterials: potential impact on course of inflammation and outcome in sepsis and meningitis. Clin Microbiol Rev. 2002, 15: 95-110.PubMedCentralCrossRefPubMed
21.
Ross RA, Brockie HC, Pertwee RG: Inhibition of nitric oxide production in RAW264.7 macrophages by cannabinoids and palmitoylethanolamide. Eur J Pharmacol. 2000, 401: 121-130.CrossRefPubMed
22.
Solorzano C, Zhu C, Battista N, Astarita G, Lodola A, Rivara S, Mor M, Russo R, Maccarrone M, Antonietti F, Duranti A, Tontini A, Cuzzocrea S, Tarzia G, Piomelli D: Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci U S A. 2009, 106: 20966-20971.PubMedCentralCrossRefPubMed
23.
Rašková H, Mašek K, Linèt O: Non-specific resistance induced by palmitoylethanolamide. Toxicon. 1972, 10: 485-490.CrossRefPubMed
24.
Mašek K, Perlík F, Klíma J, Kahlich R: Prophylactic efficacy of N-2- hydroxyethyl palmitamide (impulsin) in acute respiratory tract infections. Eur J Clin Pharmacol. 1974, 7: 415-419.CrossRefPubMed
25.
Plesník V, Havrlantová M, Jancová J, Januska J, Macková O: Impulsin in the prevention of acute respiratory diseases in school children. Cesk Pediatr. 1977, 6: 365-369.
26.
Cabellos C, Verdaguer R, Olmo M, Fernández-Sabe N, Cisnal M, Ariza J, Gudiol F, Viladrich PF: Community-acquired bacterial meningitis in elderly patients: experience over 30 years. Medicine (Baltimore). 2009, 88: 115-119.CrossRef
27.
Gaschignard J, Levy C, Romain O, Cohen R, Bingen E, Aujard Y, Boileau P: Neonatal bacterial meningitis: 444 cases in 7 years. Pediatr Infect Dis J. 2011, 30: 212-217.CrossRefPubMed
28.
Weinberger B, Grubeck-Loebenstein B: Vaccines for the elderly. Clin Microbiol Infect. 2012, 18 (Suppl 5): 100-108.CrossRefPubMed
29.
Talati AJ, Kim HJ, Kim YI, Yi AK, English BK: Role of bacterial DNA in macrophage activation by group B streptococci. Microbes Infect. 2008, 10: 1106-1113.CrossRefPubMed
30.
Ribes S, Ebert S, Regen T, Agarwal A, Tauber SC, Czenik D, Spreer A, Bunkowski S, Eiffert H, Hanisch UK, Hammerschmidt S, Nau R: Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated Streptococcus pneumoniae by murine microglia. Infect Immun. 2010, 78: 865-871.PubMedCentralCrossRefPubMed
31.
Ribes S, Ebert S, Czesnik D, Regen T, Zeug A, Bunkowski S, Mildner A, Eiffert H, Hanisch UK, Hammerschmidt S, Nau R: Toll-like receptor prestimulation increases phagocytosis of Escherichia coli DH5alpha and Escherichia coli K1 strains by murine microglial cells. Infect Immun. 2009, 77: 557-564.PubMedCentralCrossRefPubMed
32.
Redlich S, Ribes S, Schutze S, Eiffert H, Nau R: Toll-like receptor stimulation increases phagocytosis of Cryptococcus neoformans by microglial cells. J Neuroinflammation. 2013, 10: 71.PubMedCentralCrossRefPubMed
33.
Krieg AM, Love-Homan L, Yi AK, Harty JT: CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol. 1998, 161: 2428-2434.PubMed
34.
Weighardt H, Feterowski C, Veit M, Rump M, Wagner H, Holzmann B: Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response. J Immunol. 2000, 165: 4537-4543.CrossRefPubMed
35.
Miyagi K, Kawakami K, Kinjo Y, Uezu U, Yamashiro S, Arakaki K: CpG oligodeoxynucleotides promote the host protective response against infection with Cryptococcus neoformans through induction of interferon-gamma production by CD4+ T cells. Clin Exp Immunol. 2005, 140: 220-229.PubMedCentralCrossRefPubMed
36.
Ribes S, Adam N, Schutze S, Regen T, Redlich S, Janova H, Borisch A, Hanisch UK, Nau R: The nucleotide-binding oligomerization domain-containing-2 ligand muramyl dipeptide enhances phagocytosis and intracellular killing of Escherichia coli K1 by Toll-like receptor agonists in microglial cells. J Neuroimmunol. 2012, 252: 16-23.CrossRefPubMed
37.
Parant M, Parant F, Chedid L: Enhancement of the neonate’s nonspecific immunity to Klebsiella infection by muramyl dipeptide, a synthetic immunoadjuvant. Proc Natl Acad Sci U S A. 1978, 75: 3395-3399.PubMedCentralCrossRefPubMed
38.
Fraser-Smith EB, Matthews TR: Protective effect of muramyl dipeptide analogs against infections of Pseudomonas aeruginosa or Candida albicans in mice. Infect Immun. 1981, 34: 676-683.PubMedCentralPubMed
39.
Sarkar K, Das PK: Protective effect of neoglycoprotein-conjugated muramyl dipeptide against Leishmania donovani infection: the role of cytokines. J Immunol. 1997, 158: 5357-5365.PubMed
40.
Krahenbuhl JL, Sharma SD, Ferraresi RW, Remington JS: Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infect Immun. 1981, 31: 716-722.PubMedCentralPubMed
41.
Matsumoto K, Ogawa H, Nagase O, Kusama T, Azuma I: Stimulation of nonspecific host resistance to infection induced by muramyldipeptides. Microbiol Immunol. 1981, 25: 1047-1058.CrossRefPubMed
42.
Namba K, Nakajima R, Otani T, Azuma I: Oral application of romurtide, a synthetic muramyl dipeptide derivative, stimulates nonspecific resistance to microbial infections and hematopoiesis in mice. Vaccine. 1996, 14: 1149-1153.CrossRefPubMed
43.
44.
45.
Iliev AI, Stringaris AK, Nau R, Neumann H: Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). FASEB J. 2004, 18: 412-414.PubMed
46.
Grandgirard D, Gaumann R, Coulibaly B, Dangy JP, Sie A, Junghanss T, Schudel H, Pluschke G, Leib SL: The causative pathogen determines the inflammatory profile in cerebrospinal fluid and outcome in patients with bacterial meningitis. Mediators Inflamm. 2013, 2013: 312476.PubMedCentralCrossRefPubMed
47.
Nau R, Gerber J, Bunkowski S, Bruck W: Axonal injury, a neglected cause of CNS damage in bacterial meningitis. Neurology. 2004, 62: 509-511.CrossRefPubMed
48.
Perry VH, Newman TA, Cunningham C: The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci. 2003, 4: 103-112.CrossRefPubMed
49.
Lehnardt S: Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. 2010, 58: 253-263.PubMed
50.
Schutze S, Loleit T, Zeretzke M, Bunkowski S, Brück W, Ribes S, Nau R: Additive microglia-mediated neuronal injury caused by amyloid-beta and bacterial TLR agonists in murine neuron-microglia co-cultures quantified by an automated image analysis using cognition network technology. J Alzheimers Dis. 2012, 31: 651-657.PubMed
51.
Nau R, Ribes S, Djukic M, Eiffert H: Strategies to increase the activity of microglia as efficient protectors of the brain against infections. Frontiers Cell Neurosci. 2014, 22: 8-138.
52.
Di PR, Impellizzeri D, Torre A, Mazzon E, Cappellani A, Faggio C, Esposito E, Trischitta F, Cuzzocrea S: Effects of palmitoylethanolamide on intestinal injury and inflammation caused by ischemia-reperfusion in mice. J Leukoc Biol. 2012, 91: 911-920.CrossRef
53.
Engelhardt B, Coisne C: Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS. 2011, 8: 4.PubMedCentralCrossRefPubMed
54.
Keppel Hesselink JM, de Boer T, Witkamp RF: Palmitoylethanolamide: a natural body-own anti-inflammatory agent, effective and safe against influenza and common cold. Int J Inflam. 2013, 2013: 151028.PubMedCentralCrossRefPubMed
Metadata
Title
Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 by macrophages and increases the resistance of mice against infections
Authors
Sandra Redlich
Sandra Ribes
Sandra Schütze
Roland Nau
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2014
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-11-108

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