Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

Gobbetti, T., Coldewey, S.M., Chen, J., McArthur, S., le Faouder, P., Cenac, N., Flower, R.J., Thiemermann, C. and Perretti, M. 2014. Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis. Proceedings of the National Academy of Sciences. 111 (52), pp. 18685-90. doi:10.1073/pnas.1410938111

TitleNonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis
AuthorsGobbetti, T., Coldewey, S.M., Chen, J., McArthur, S., le Faouder, P., Cenac, N., Flower, R.J., Thiemermann, C. and Perretti, M.
Abstract

Sepsis is characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state, defining a complex clinical scenario that explains the lack of successful therapeutic options. Here we tested whether the formyl-peptide receptor 2/3 (Fpr2/3)-ortholog to human FPR2/ALX (receptor for lipoxin A4)-exerted regulatory and organ-protective functions in experimental sepsis. Coecal ligature and puncture was performed to obtain nonlethal polymicrobial sepsis, with animals receiving antibiotics and analgesics. Clinical symptoms, temperature, and heart function were monitored up to 24 h. Peritoneal lavage and plasma samples were analyzed for proinflammatory and proresolving markers of inflammation and organ dysfunction. Compared with wild-type mice, Fpr2/3(-/-) animals exhibited exacerbation of disease severity, including hypothermia and cardiac dysfunction. This scenario was paralleled by higher levels of cytokines [CXCL1 (CXC receptor ligand 1), CCL2 (CC receptor ligand 2), and TNFα] as quantified in cell-free biological fluids. Reduced monocyte recruitment in peritoneal lavages of Fpr2/3(-/-) animals was reflected by a higher granulocyte/monocyte ratio. Monitoring Fpr2/3(-/-) gene promoter activity with a GFP proxy marker revealed an over threefold increase in granulocyte and monocyte signals at 24 h post-coecal ligature and puncture, a response mediated by TNFα. Treatment with a receptor peptido-agonist conferred protection against myocardial dysfunction in wild-type, but not Fpr2/3(-/-), animals. Therefore, coordinated physio-pharmacological analyses indicate nonredundant modulatory functions for Fpr2/3 in experimental sepsis, opening new opportunities to manipulate the host response for therapeutic development.

JournalProceedings of the National Academy of Sciences
Journal citation111 (52), pp. 18685-90
ISSN1091-6490
Year2014
PublisherNational Academy of Sciences
Digital Object Identifier (DOI)doi:10.1073/pnas.1410938111
Publication dates
Published15 Dec 2014

Related outputs

The restorative role of annexin A1 at the blood–brain barrier
McArthur, S., Azevedo Loila, R, Maggioli, E, Errede, M, Virgintino, D and Solito, E 2016. The restorative role of annexin A1 at the blood–brain barrier. Fluids & Barriers of the CNS. 13, pp. 17-33. doi:10.1186/s12987-016-0043-0

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory
Virdee, K., Kentrop, J., Jupp, B., Venus, B., Hensman, D., McArthur, S., Wilkinson, J., Robbins, T.W., Gillies, G.E. and Dalley, J.W. 2016. Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory. Psychopharmacology. 233 (21), pp. 3751-3761. doi:10.1007/s00213-016-4405-8

Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking
Maggioli, E., McArthur, S., Mauro, C., Kieswich, J., Kusters, D.H.M., Reutelingsperger, C.P.M., Yaqoob, M.M. and Solito, E. 2015. Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking. Brain Behavior & Immunity. 51, p. 212–222. doi:10.1016/j.bbi.2015.08.020

Definition of a Novel Pathway Centered on Lysophosphatidic Acid To Recruit Monocytes during the Resolution Phase of Tissue Inflammation.
McArthur, S., Gobbetti, T., Kusters, D.H.M., Reutelingsperger, C.P.M., Flower, R.J. and Perretti, M. 2015. Definition of a Novel Pathway Centered on Lysophosphatidic Acid To Recruit Monocytes during the Resolution Phase of Tissue Inflammation. Journal of Immunology. 195 (3), pp. 1139-1151. doi:10.4049/jimmunol.1500733

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment
McArthur, S., Pienaar, I.S., Siddiqi, S.M., Gillies, G.E. and Mazhar-Siddiqi, S. 2015. Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment. Brain Stucture & Function. doi:10.1007/s00429-015-1049-0

Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone
Shende Vishvesh, McArthur, S. and Opacka-Juffry Jolanta 2015. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone. Neural Plasticity. 2015, p. Article ID 694347. doi:10.1155/2015/694347

Identification of a Novel Recycling Sequence in the C-tail of FPR2/ALX Receptor: Association with Cell Protection from Apoptosis
Thompson, D., McArthur, S., Hislop, J.N., Flower, R.J., Perretti, M. and James N. Hislop 2014. Identification of a Novel Recycling Sequence in the C-tail of FPR2/ALX Receptor: Association with Cell Protection from Apoptosis. Journal of Biological Chemistry. 289 (52), pp. 36166-78. doi:10.1074/jbc.M114.612630

Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience
Virdee, K., McArthur, S., Brischoux, F., Caprioli, D., Ungless, M.A., Robbins, T.W., Dalley, J.W. and Gillies, G.E. 2014. Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 39 (2), pp. 339-350. doi:10.1038/npp.2013.196

Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice
Locatelli, I., Sutti, S., Jindal, A., Vacchiano, M., Bozzola, C., Reutelingsperger, C.P.M., Kusters, D.H.M., Bena, S., Parola, M., Paternostro, C., Bugianesi, E., McArthur, S., Albano, E. and Perretti, M. 2014. Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice. Hepatology. 60 (2), pp. 531-544. doi:10.1002/hep.27141

Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: a molecular, cellular and behavioral analysis
Gillies, G.E., Virdee, K., McArthur, S. and Dalley, J.W. 2014. Sex-dependent diversity in ventral tegmental dopaminergic neurons and developmental programing: a molecular, cellular and behavioral analysis. Neuroscience. 282C, pp. 69-85. doi:10.1016/j.neuroscience.2014.05.033

Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses
Cooray, S.N., Gobbetti, T., Montero-Melendez, T., McArthur, S., Thompson, D., Clark, A.J.L., Flower, R.J. and Perretti, M. 2013. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proceedings of the National Academy of Sciences of the United States of America. 110 (45), pp. 18232-18237. doi:10.1073/pnas.1308253110

Prazosin, an α(1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease
Katsouri, L., Vizcaychipi, M.P., McArthur, S., Harrison, I., Suárez-Calvet, M., Lleo, A., Lloyd, D.G., Ma, D. and Sastre, M. 2013. Prazosin, an α(1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease. Neurobiology of Aging. 34 (4), pp. 1105-15. doi:10.1016/j.neurobiolaging.2012.09.010

Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity
Nadkarni, S. and McArthur, S. 2013. Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Current opinion in pharmacology. 13 (4), pp. 576-581. doi:10.1016/j.coph.2013.05.007

Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications
Cristante, E., McArthur, S., Mauro, C., Maggioli, E., Romero, I.A., Wylezinska-Arridge, M., Couraud, P.O., Lopez-Tremoleda, J., Christian, H.C., Weksler, B.B., Malaspina, A. and Solito, E. 2013. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proceedings of the National Academy of Sciences of the United States of America. 110 (3), pp. 832-841. doi:10.1073/pnas.1209362110

Chemerin15 inhibits neutrophil-mediated vascular inflammation and myocardial ischemia-reperfusion injury through ChemR23
Cash, J.L., Bena, S., Headland, S.E., McArthur, S., Brancaleone, V. and Perretti, M. 2013. Chemerin15 inhibits neutrophil-mediated vascular inflammation and myocardial ischemia-reperfusion injury through ChemR23. EMBO reports. 14 (11), pp. 999-1007. doi:10.1038/embor.2013.138

Annexin A1 N-terminal derived Peptide ac2-26 exerts chemokinetic effects on human neutrophils
Dalli, J., Montero-Melendez, T., McArthur, S. and Perretti, M. 2012. Annexin A1 N-terminal derived Peptide ac2-26 exerts chemokinetic effects on human neutrophils. Frontiers in Pharmacology. 3, p. 28. doi:10.3389/fphar.2012.00028

Novel ontogenetic patterns of sexual differentiation in arcuate nucleus GHRH neurons revealed in GHRH-enhanced green fluorescent protein transgenic mice
McArthur, S., Robinson, I.C. and Gillies, G.E. 2011. Novel ontogenetic patterns of sexual differentiation in arcuate nucleus GHRH neurons revealed in GHRH-enhanced green fluorescent protein transgenic mice. Endocrinology. 152 (2), pp. 607-617. doi:10.1210/en.2010-0798

Peripheral vs. central sex steroid hormones in experimental Parkinson's disease
McArthur, S. and Gillies, G.E. 2011. Peripheral vs. central sex steroid hormones in experimental Parkinson's disease. Frontiers in endocrinology. 2, p. 82. doi:10.3389/fendo.2011.00082

Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines
Gillies, G.E. and McArthur, S. 2010. Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacological reviews. 62 (2), pp. 155-198. doi:10.1124/pr.109.002071

Anti-allergic drugs and the Annexin-A1 system
Yazid, S., Ayoub, S.S., Solito, E., McArthur, S., Vo, P., Dufton, N. and Flower, R.J. 2010. Anti-allergic drugs and the Annexin-A1 system. Pharmacological reports. 62 (3), pp. 511-517. doi:10.1016/S1734-1140(10)70307-8

Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia
McArthur, S., Cristante, E., Paterno, M., Christian, H.C., Roncaroli, F., Gillies, G.E. and Solito, E. 2010. Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. Journal of Immunology. 185 (10), pp. 6317-6328. doi:10.4049/jimmunol.1001095

Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: a contribution to sex-specific neuroprotection by estrogens
Gillies, G.E. and McArthur, S. 2010. Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: a contribution to sex-specific neuroprotection by estrogens. Hormones and behavior. 57 (1), pp. 23-34. doi:10.1016/j.yhbeh.2009.06.002

Cromoglycate drugs suppress eicosanoid generation in U937 cells by promoting the release of Anx-A1
Yazid, S., Solito, E., Christian, H.C., McArthur, S., Goulding, N. and Flower, R.J. 2009. Cromoglycate drugs suppress eicosanoid generation in U937 cells by promoting the release of Anx-A1. Biochemical Pharmacology. 77 (12), pp. 1814-1826. doi:10.1016/j.bcp.2009.03.010

Annexin A1 regulates hormone exocytosis through a mechanism involving actin reorganization
McArthur, S., Yazid, S., Christian, H.C., Sirha, R., Flower, R.J., Buckingham, J.C. and Solito, E. 2009. Annexin A1 regulates hormone exocytosis through a mechanism involving actin reorganization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 23 (11), pp. 4000-4010. doi:10.1096/fj.09-131391

Annexin A1 in the brain: undiscovered roles?
Solito, E., McArthur, S., Christian, H.C., Gavins, F.N.E., Buckingham, J.C. and Gillies, G.E. 2008. Annexin A1 in the brain: undiscovered roles? Trends in Pharmacological Sciences. 29 (3), pp. 135-42. doi:10.1016/j.tips.2007.12.003

Striatal susceptibility to a dopaminergic neurotoxin is independent of sex hormone effects on cell survival and DAT expression but is exacerbated by central aromatase inhibition
McArthur, S., Murray, H.E., Dhankot, A., Dexter, D.T. and Gillies, G.E. 2007. Striatal susceptibility to a dopaminergic neurotoxin is independent of sex hormone effects on cell survival and DAT expression but is exacerbated by central aromatase inhibition. Journal of Neurochemistry. 100 (3), pp. 678-692. doi:10.1111/j.1471-4159.2006.04226.x

The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner
McArthur, S., McHale, E. and Gillies, G.E. 2007. The size and distribution of midbrain dopaminergic populations are permanently altered by perinatal glucocorticoid exposure in a sex- region- and time-specific manner. Neuropsychopharmacology. 32 (7), pp. 1462-1476. doi:10.1038/sj.npp.1301277

Perinatal glucocorticoid treatment disrupts the hypothalamo-lactotroph axis in adult female, but not male, rats
McArthur, S., Siddique, Z.L., Christian, H.C., Capone, G., Theogaraj, E., John, C.D., Smith, S.F., Morris, J.F., Buckingham, J.C. and Gillies, G.E. 2006. Perinatal glucocorticoid treatment disrupts the hypothalamo-lactotroph axis in adult female, but not male, rats. Endocrinology. 147 (4), pp. 1904-1915. doi:10.1210/en.2005-1496

Altered mesencephalic dopaminergic populations in adulthood as a consequence of brief perinatal glucocorticoid exposure
McArthur, S., McHale, E., Dalley, J.W., Buckingham, J.C. and Gillies, G.E. 2005. Altered mesencephalic dopaminergic populations in adulthood as a consequence of brief perinatal glucocorticoid exposure. Journal of Neuroendocrinology. 17 (8), pp. 475-482. doi:10.1111/j.1365-2826.2005.01331.x

Sex dimorphisms in the neuroprotective effects of estrogen in an animal model of Parkinson's disease
Gillies, G.E., Murray, H.E., Dexter, D.T. and McArthur, S. 2004. Sex dimorphisms in the neuroprotective effects of estrogen in an animal model of Parkinson's disease. Pharmacology, biochemistry, and behavior. 78 (3), pp. 513-522. doi:10.1016/j.pbb.2004.04.022

Dose- and sex-dependent effects of the neurotoxin 6-hydroxydopamine on the nigrostriatal dopaminergic pathway of adult rats: differential actions of estrogen in males and females
Murray, H.E., Pillai, A.V., McArthur, S., Razvi, N., Datla, K.P., Dexter, D.T. and Gillies, G.E. 2003. Dose- and sex-dependent effects of the neurotoxin 6-hydroxydopamine on the nigrostriatal dopaminergic pathway of adult rats: differential actions of estrogen in males and females. Neuroscience. 116 (1), pp. 213-222. doi:10.1016/S0306-4522(02)00578-X

Permalink - https://westminsterresearch.westminster.ac.uk/item/95653/nonredundant-protective-properties-of-fpr2-alx-in-polymicrobial-murine-sepsis


Share this
Tweet
Email