Lord, Megan S.

Petrey, Aaron C.

Reijmers, Rogier M.

Troeberg, Linda

English

University of East Anglia digital repository

EDITORIALpublished: 15 October 2020doi: 10.3389/fimmu.2020.595867Frontiers in Immunology | www.frontiersin.org 1 October 2020 | Volume 11 | Article 595867Edited and reviewed by:Silvano Sozzani,Sapienza University of Rome, Italy*Correspondence:Rogier M. Reijmersr.reijmers@lumicks.comLinda Troebergl.troeberg@uea.ac.ukMegan S. Lordm.lord@unsw.edu.auAaron C. Petreyaaron.petrey@u2m2.utah.eduSpecialty section:This article was submitted toCytokines and Soluble Mediators inImmunity,a section of the journalFrontiers in ImmunologyReceived: 17 August 2020Accepted: 08 September 2020Published: 15 October 2020Citation:Reijmers RM, Troeberg L, Lord MSand Petrey AC (2020) Editorial:Proteoglycans andGlycosaminoglycan Modification inImmune Regulation and Inflammation.Front. Immunol. 11:595867.doi: 10.3389/fimmu.2020.595867Editorial: Proteoglycans andGlycosaminoglycan Modification inImmune Regulation and InflammationRogier M. Reijmers 1*, Linda Troeberg 2*, Megan S. Lord 3* and Aaron C. Petrey 4,5*1 LUMICKS B.V., Amsterdam, Netherlands, 2Norwich Medical School, University of East Anglia, Norwich, United Kingdom,3Graduate School of Biomedical Engineering, University of New South Wales Sydney, Sydney, NSW, Australia, 4University ofUtah Molecular Medicine Program, Salt Lake City, UT, United States, 5Division of Microbiology and Immunology, Departmentof Pathology, University of Utah, Salt Lake City, UT, United StatesKeywords: glycosaminoglycan (GAG), proteoglycans (PG), immune response, inflammation, heparan sulfate (HS),chondroitin sulfate (CS), dermatan sulfate (DS), hyaluronanEditorial on the Research TopicProteoglycans and GlycosaminoglycanModification in Immune Regulation and InflammationWhile many publications cover proteoglycan and glycosaminoglycan (GAG) research each year,to date there is still limited knowledge about the specific roles of these macromolecules in theregulation of immune responses and homeostasis. More specifically, the transcriptional controlis understudied and largely unknown (1). For this reason, we initiated this Research Topicfor Frontiers in Immunology, and challenged scientists to provide findings that uncover novelfunctions or summarize recent progress that connect these two fields of research. Our collectionof 16 manuscripts consists of 7 Original Research papers, one Perspective, one Mini Review, and7 Reviews covering different aspects of proteoglycan biology in immune processes, which aresummarized below.Proteoglycans are ubiquitously expressed intracellularly, on the cell surface and in theextracellularmatrix. Attached to their core are one or amultitude of covalently linked linear anionicGAGs, which are subject to an array of synthetic and post-synthetic enzymatic modifications,leading to an almost infinite combination of configurations, each potentially harboring specificfunctions (2). As such, precise GAG modifications have been attributed to drive interactions withimmune cells, pathogens, and specific protein ligands, while functions have also been attributedto the core proteins. Likewise, the immune system is extremely diverse with many different celltypes and immunomodulators, such as chemokines and cytokines, each having specific and uniquefunctions. All of these components need to be kept in strict balance and require tight spatiotemporalregulation to avoid development of autoimmunity or cancer, while combatting a limitless numberof pathogens. Understanding this complexity is the greatest challenge in the field and requiresdetailed structural analysis of GAGs and proteoglycans (3).Reijmers et al. Editorial: Proteoglycans in Immunity and InflammationRajarathnam and Desai reviewed recent progress inunderstanding the molecular basis of chemokine interactionswith GAGs and their CXCR1 and CXCR2 receptors. They arguethat the range of GAG-binding affinities and geometries confersremarkable selectivity on the in vivo phenotype of individualchemokines, and that understanding these interactions iscritical for clinical application. Crijns et al. more broadlyaddress chemokine-GAG interactions, and suggest that limitinginflammation using different approaches like chemokine-derivedGAG-binding peptides or dominant-negative chemokinemutants, might be beneficial, especially if required to reduce theinflammatory response, rather than completely eliminating it.Specific effects of GAGs on inflammatory processes wereaddressed by several authors. For example, Talsma et al. extendedour understanding of GAG effects on complement activationby demonstrating that heparin/heparan sulfate oligosaccharidesinhibit the lectin pathway via inhibiting the activity of serineprotease MASP-2 that cleaves C4. This work may enable thedevelopment of glycan-based inhibitors of the lectin pathwaywith therapeutic value. Arokiasamy, King et al. profiled theglycocalyx of lymphatic vessel endothelial cells, which is lesswell-understood than the glycocalyx associated with vascularendothelial cells. They showed that the lymphatic glycocalyxof murine cremaster muscles is remodeled in response toTNF-mediated inflammation. Blocking heparanase-mediateddegradation of HS had no effect on neutrophil migrationthrough the lymphatic vessels; but reduced lymphatic drainageof interstitial fluid. The responses and function of the lymphaticglycocalyx is thus distinct from that of blood vessels. El Masriet al. explored the role of SULFs in inflammation. Despiteclear evidence for critical functions of these enzymes in variouspathologies including cancer, the roles of SULFs in inflammatoryprocesses are under-appreciated. To advance this field, furtherinvestigations are needed to fully understand their spatial andtemporal expression and activity. How this could be strategicallyadvanced in the near future is discussed in this Perspective article.Use of disease models is progressing our understanding ofthe role of GAGs in complex in vivo scenarios. Pessentheineret al. summarize the broad role of proteoglycans in obesity-related inflammation. Each class of proteoglycan is discussed,including their enzymatic modifications, and key clinical studiesare highlighted implicating proteoglycans as therapeutic targetsand biomarkers. Despite limited knowledge of syndecans inobesity-related inflammation, it is clear that syndecans aremajor players in inflammation. Gopal concisely reviewed thecharacteristics of syndecans, especially syndecan-1, -2 and -4,explaining their diverse role at the cell surface or as solubleproteins. Arokiasamy, Balderstone et al. focused on the roleof syndecan-3 in inflammation and angiogenesis, discussingits impact in several distinct disease types and emphasizingthat interactions with the GAG chains make syndecan-3 aninflammatory mediator.In addition to research on HS, we are beginning to appreciatethe roles of chondroitin sulfate (CS) in regulating inflammation.Hatano and Watanabe reviewed the roles of CS produced byantigen presenting cells, in contrast to the more widely studiedroles of heparan sulfate (HS) and hyaluronan (HA). Importantly,this review suggests a structure-function relationship for CSbased on sulfation with highly sulfated CS, such as CS-C, CS-D, and CS-E, possessing anti-inflammatory properties while thelesser sulfated CS-A possesses both pro- and anti-inflammatoryproperties. In addition, chain length is a determinant of functionwith oligosaccharides exhibiting pro-inflammatory properties.Wight et al. provide a comprehensive review on the regulatoryroles of the HA-binding proteoglycan versican in the contextof immunity and inflammation. The authors summarize howversican and its five different isoforms vary in function, andthough not all contain CS chains, each mediates complex rolesfrom development to inflammation by virtue of interacting witha host of diverse immune receptors. They provide insight intocell-type specific functions of versican and highlight how CScontaining glycoforms allow versican to function as either a pro-or anti-inflammatory proteoglycan.Although HA lacks the sulfation shared by the other GAGs,investigation into its regulatory role in inflammatory processescontinues to reveal unexpected findings. Dong et al. report apreviously unknown link between the HA receptor CD44 andclearance of lung surfactant by alveolar macrophages (AM),which constitutively bind to HA. Loss of CD44 in mice leads toreduced numbers of AMs, and dysregulation of genes involvedin cholesterol metabolism. In addition, CD44 deficiency resultsin a buildup of lipid surfactant, foam-cell AMs, and oxidizedlipids which exacerbate lung damage and inflammation. Reeveset al. demonstrate that RSV infection of pediatric human lungfibroblasts results in the formation of an HA-enriched ECMcapable of recruiting mast cells and augmenting expression ofmast cell proteases. Further, by disrupting HA synthesis orHA binding, the authors demonstrate that increased proteaseexpression depends on mast cell interaction with the HA-matrixproduced by infected cells.Besides the impact on cells and immune modulators, effectsof GAGs on bacterial pathogenesis were also explored. Martínet al. report that adhesion of L. salivarius Lv72 to HeLacells induced expression of proteoglycan core proteins butreduced glycosaminoglycan chain biosynthesis by the HeLa cells.In addition, L. salivarius Lv72 increased expression of oppAwhich aids in adhesion to mucosal cells. These results suggestcommunication between mucosa and microbiota. Galeev et al.demonstrated that proteoglycans not only play a role in bacterialadhesion and uptake by epithelial cells, but that they also playa critical role in the survival of bacteria once internalized viacontrol of intracellular trafficking and endo-lysosomal fusion.Clinical translation of GAG-based therapies is an excitingchallenge. PG545, a synthetic heparanase inhibitor, has beendemonstrated to affect tumor viability by preventing angiogenesisand non-neoplastic inflammatory disorders. PG545 acts throughcompeting for GAG binding, and Koliesnik et al. showthat it selectively induces Treg development and inhibits theformation of Th17 cells in vitro and during in vivo delayedtype hypersensitivity (DTH). Unexpectedly, these effects wereindependent of heparanase, but the results support clinicalapplication of PG545 in inflammatory responses associatedwith DTH. Furthermore, use of human milk glycans suchas HA have captured attention for their potential as naturalFrontiers in Immunology | www.frontiersin.org 2 October 2020 | Volume 11 | Article 595867Reijmers et al. Editorial: Proteoglycans in Immunity and Inflammationproducts to enhance immune responses and their safety astherapeutic modalities. Kim and de la Motte summarize severalpre-clinical studies highlighting the known roles of HA inintestinal host defense, detailing the receptors which mediatedownstream mechanisms activated by exogenous HA includingbarrier function and anti-microbial effects.Our Research Topic underscores the diverse role thatproteoglycans have in inflammation and how they controldifferent aspects of immunological processes. However,it also demonstrates that there is still much to discoverabout the specific mechanisms of their action, includingtranscriptional and translational regulation of proteoglycan andGAG biosynthesis (1).AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct andintellectual contribution to the work, and approved itfor publication.ACKNOWLEDGMENTSWe would like to thank all authors for their contributionto our Research Topic. This work was supported by VersusArthritis (grant 21245, LT) and National Institutes of Health(HL135265, AP).REFERENCES1. Weiss RJ, Spahn PN, Toledo AG, Chiang AWT, Kellman BP, Li J, et al. ZNF263is a transcriptional regulator of heparin and heparan sulfate biosynthesis. ProcNatl Acad Sci USA. (2020) 117:9311–7. doi: 10.1073/pnas.19208801172. Bishop JR, Schiksz M, Esko JD. Heparan sulphate proteoglycans fine-tunemammalian physiology. Nature. (2007) 446:1030–7. doi: 10.1038/nature058173. Kjellén L, Lindahl U. Specificity of glycosaminoglycan-protein interactions.Curr Opin Struct Biol. (2018) 50:101–8. doi: 10.1016/j.sbi.2017.12.011Conflict of Interest: RR was employed by the company LUMICKS. ML is aDirector of Glycos Pty Ltd, which is focused on the generation of bioengineeredglycosaminoglycans as therapeutics.The remaining authors declare that the research was conducted in the absence ofany commercial or financial relationships that could be construed as a potentialconflict of interest.Copyright © 2020 Reijmers, Troeberg, Lord and Petrey. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Immunology | www.frontiersin.org 3 October 2020 | Volume 11 | Article 595867

Editorial: Proteoglycans and Glycosaminoglycan Modification in Immune Regulation and Inflammation

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Editorial: Proteoglycans and Glycosaminoglycan Modification in Immune Regulation and Inflammation

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