Pro-resolving Mediators Promote Resolution in a Human Skin Model of UV-killed Escherichia Coli-driven Acute Inflammation

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2018 Mar 23

PMID 29563331

Citations 41

Authors

Madhur P Motwani

Romain A Colas

Marc J George

Julia D Flint

Jesmond Dalli

Angela Richard-Loendt

Roel Ph De Maeyer

Charles N Serhan

Derek W Gilroy

Affiliations

Soon will be listed here.

Abstract

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

Citing Articles

The Role of Endogenous Specialized Proresolving Mediators in Mast Cells and Their Involvement in Inflammation and Resolution.

Fukuishi N, Takahama K, Kurosaki H, Ono S, Asai H Int J Mol Sci. 2025; 26(4).

PMID: 40003957 PMC: 11855587. DOI: 10.3390/ijms26041491.

The translational potential of inflammation-induced skin blister human models in exploring the pathogenesis of periodontitis and its systemic health implications.

Irwandi R, Marruganti C, Collins G, de Souza Carvalho J, Gilroy D, DAiuto F Front Immunol. 2024; 15:1469828.

PMID: 39737182 PMC: 11682961. DOI: 10.3389/fimmu.2024.1469828.

A new model measuring bacterial phagocytosis and phagolysosomal oxidation in humans using the intradermal injection of methylene blue-labeled Escherichia coli.

Collins G, de Souza Carvalho J, Jayasinghe S, Gumuliauskaite U, Lowe D, Thomas D J Leukoc Biol. 2024; 117(2).

PMID: 39412158 PMC: 11879004. DOI: 10.1093/jleuko/qiae217.

Current Insights into Tissue Injury of Giant Cell Arteritis: From Acute Inflammatory Responses towards Inappropriate Tissue Remodeling.

Palamidas D, Chatzis L, Papadaki M, Gissis I, Kambas K, Andreakos E Cells. 2024; 13(5.

PMID: 38474394 PMC: 10930978. DOI: 10.3390/cells13050430.

Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries.

Levy E, Kim A, Werlin E, Chen M, Sansbury B, Spite M JVS Vasc Sci. 2023; 4:100126.

PMID: 38045567 PMC: 10692706. DOI: 10.1016/j.jvssci.2023.100126.

References

English J, Norris P, Hodges R, Dartt D, Serhan C . Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics. Prostaglandins Leukot Essent Fatty Acids. 2017; 117:17-27. PMC: 5329889. DOI: 10.1016/j.plefa.2017.01.004. View

Schmid M, Gemperle C, Rimann N, Hersberger M . Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32. J Immunol. 2016; 196(8):3429-37. DOI: 10.4049/jimmunol.1501701. View

Chiang N, Fredman G, Backhed F, Oh S, Vickery T, Schmidt B . Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature. 2012; 484(7395):524-8. PMC: 3340015. DOI: 10.1038/nature11042. View

Franceschi C, Campisi J . Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014; 69 Suppl 1:S4-9. DOI: 10.1093/gerona/glu057. View

Serhan C, Savill J . Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005; 6(12):1191-7. DOI: 10.1038/ni1276. View

Rajakariar R, Hilliard M, Lawrence T, Trivedi S, Colville-Nash P, Bellingan G . Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2. Proc Natl Acad Sci U S A. 2007; 104(52):20979-84. PMC: 2409252. DOI: 10.1073/pnas.0707394104. View

Maderna P, Cottell D, Toivonen T, Dufton N, Dalli J, Perretti M . FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis. FASEB J. 2010; 24(11):4240-9. PMC: 4338542. DOI: 10.1096/fj.10-159913. View

Monaco C, Nanchahal J, Taylor P, Feldmann M . Anti-TNF therapy: past, present and future. Int Immunol. 2014; 27(1):55-62. PMC: 4279876. DOI: 10.1093/intimm/dxu102. View

Gilroy D, Edin M, De Maeyer R, Bystrom J, Newson J, Lih F . CYP450-derived oxylipins mediate inflammatory resolution. Proc Natl Acad Sci U S A. 2016; 113(23):E3240-9. PMC: 4988604. DOI: 10.1073/pnas.1521453113. View

10.

Bondue B, Vosters O, de Nadai P, Glineur S, De Henau O, Luangsay S . ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia. PLoS Pathog. 2011; 7(11):e1002358. PMC: 3207933. DOI: 10.1371/journal.ppat.1002358. View

11.

Serhan C . Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014; 510(7503):92-101. PMC: 4263681. DOI: 10.1038/nature13479. View

12.

Planaguma A, Kazani S, Marigowda G, Haworth O, Mariani T, Israel E . Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med. 2008; 178(6):574-82. PMC: 2542432. DOI: 10.1164/rccm.200801-061OC. View

13.

Zhang M, Sansbury B, Hellmann J, Baker J, Guo L, Parmer C . Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. Circulation. 2016; 134(9):666-680. PMC: 5214591. DOI: 10.1161/CIRCULATIONAHA.116.021894. View

14.

Motwani M, Flint J, De Maeyer R, Fullerton J, Smith A, Marks D . Novel translational model of resolving inflammation triggered by UV-killed E. coli. J Pathol Clin Res. 2016; 2(3):154-65. PMC: 4958736. DOI: 10.1002/cjp2.43. View

15.

Krishnamoorthy N, Burkett P, Dalli J, Abdulnour R, Colas R, Ramon S . Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J Immunol. 2014; 194(3):863-7. PMC: 4297713. DOI: 10.4049/jimmunol.1402534. View

16.

Luangsay S, Wittamer V, Bondue B, De Henau O, Rouger L, Brait M . Mouse ChemR23 is expressed in dendritic cell subsets and macrophages, and mediates an anti-inflammatory activity of chemerin in a lung disease model. J Immunol. 2009; 183(10):6489-99. DOI: 10.4049/jimmunol.0901037. View

17.

Poon I, Lucas C, Rossi A, Ravichandran K . Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014; 14(3):166-80. PMC: 4040260. DOI: 10.1038/nri3607. View

18.

Ariel A, Fredman G, Sun Y, Kantarci A, Van Dyke T, Luster A . Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol. 2006; 7(11):1209-16. PMC: 1797066. DOI: 10.1038/ni1392. View

19.

Jamieson T, Cook D, Nibbs R, Rot A, Nixon C, McLean P . The chemokine receptor D6 limits the inflammatory response in vivo. Nat Immunol. 2005; 6(4):403-11. DOI: 10.1038/ni1182. View

20.

Sasaki A, Fukuda H, Shiida N, Tanaka N, Furugen A, Ogura J . Determination of ω-6 and ω-3 PUFA metabolites in human urine samples using UPLC/MS/MS. Anal Bioanal Chem. 2015; 407(6):1625-39. DOI: 10.1007/s00216-014-8412-5. View