{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T19:52:00Z","timestamp":1784317920003,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T00:00:00Z","timestamp":1700092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DFG","award":["GRK2336 TP06, TP01"],"award-info":[{"award-number":["GRK2336 TP06, TP01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Macrophages are a highly versatile and heterogenic group of immune cells, known for their involvement in inflammatory reactions. However, our knowledge about distinct subpopulations of macrophages and their specific contribution to the resolution of inflammation remains incomplete. We have previously shown, in an in vivo peritonitis model, that inhibition of the synthesis of the pro-inflammatory lipid mediator prostaglandin E2 (PGE2) attenuates efficient resolution of inflammation. PGE2 levels during later stages of the inflammatory process further correlate with expression of the hyaluronan (HA) receptor Lyve1 in peritoneal macrophages. In the present study, we therefore aimed to understand if PGE2 might contribute to the regulation of Lyve1 and how this might impact inflammatory responses. In line with our in vivo findings, PGE2 synergized with dexamethasone to enhance Lyve1 expression in bone marrow-derived macrophages, while expression of the predominant hyaluronan receptor CD44 remained unaltered. PGE2-mediated Lyve1 upregulation was strictly dependent on PGE2 receptor EP2 signaling. While PGE2\/dexamethasone-treated macrophages, despite their enhanced Lyve1 expression, did not show inflammatory responses upon stimulation with low (LMW) or high-molecular-weight hyaluronan (HMW)-HA, they were sensitized towards LMW-HA-dependent augmentation of lipopolysaccharide (LPS)-induced inflammatory responses. Thus, Lyve1-expressing macrophages emerged as a subpopulation of macrophages integrating inflammatory stimuli with extracellular matrix-derived signals.<\/jats:p>","DOI":"10.3390\/biology12111441","type":"journal-article","created":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T07:11:27Z","timestamp":1700118687000},"page":"1441","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Prostaglandin E2 Boosts the Hyaluronan-Mediated Increase in Inflammatory Response to Lipopolysaccharide by Enhancing Lyve1 Expression"],"prefix":"10.3390","volume":"12","author":[{"given":"Pauline","family":"Hog","sequence":"first","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Kuntschar","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rappl","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2437-5595","authenticated-orcid":false,"given":"Arnaud","family":"Huard","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7529-1952","authenticated-orcid":false,"given":"Andreas","family":"Weigert","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany"},{"name":"Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8237-2841","authenticated-orcid":false,"given":"Bernhard","family":"Br\u00fcne","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany"},{"name":"Frankfurt Cancer Institute, Goethe University Frankfurt, 60596 Frankfurt, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology, 60596 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1952-5259","authenticated-orcid":false,"given":"Tobias","family":"Schmid","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"699563","DOI":"10.3389\/fimmu.2021.699563","article-title":"DAMPs and Innate Immune Training","volume":"12","author":"Jentho","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and Physiological Roles of Inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1038\/s41467-018-05800-6","article-title":"Resolution of Chronic Inflammatory Disease: Universal and Tissue-Specific Concepts","volume":"9","author":"Schett","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1172\/JCI44490","article-title":"An Unrestrained Proinflammatory M1 Macrophage Population Induced by Iron Impairs Wound Healing in Humans and Mice","volume":"121","author":"Sindrilaru","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10340","DOI":"10.1073\/pnas.0604260103","article-title":"Monocyte Accumulation in Mouse Atherogenesis Is Progressive and Proportional to Extent of Disease","volume":"103","author":"Swirski","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1172\/JCI97950","article-title":"The Role of Non-Resolving Inflammation in Atherosclerosis","volume":"128","author":"Kasikara","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1182\/blood-2014-03-562710","article-title":"Resolution of Acute Inflammation Bridges the Gap between Innate and Adaptive Immunity","volume":"124","author":"Newson","year":"2014","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.4049\/jimmunol.164.12.6166","article-title":"M-1\/M-2 Macrophages and the Th1\/Th2 Paradigm","volume":"164","author":"Mills","year":"2000","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaau0964","DOI":"10.1126\/science.aau0964","article-title":"Two Distinct Interstitial Macrophage Populations Coexist across Tissues in Specific Subtissular Niches","volume":"363","author":"Chakarov","year":"2019","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","article-title":"The Chemokine System in Diverse Forms of Macrophage Activation and Polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11926-018-0725-5","article-title":"Macrophages, Wound Healing, and Fibrosis: Recent Insights","volume":"20","author":"Smigiel","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1165\/rcmb.2012-0366MA","article-title":"Identification of Myeloid Cell Subsets in Murine Lungs Using Flow Cytometry","volume":"49","author":"Zaynagetdinov","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.yexcr.2016.03.007","article-title":"Identification of Neutrophil Surface Marker Changes in Health and Inflammation Using High-Throughput Screening Flow Cytometry","volume":"342","author":"Lakschevitz","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.immuni.2020.05.014","article-title":"Determinants of Resident Tissue Macrophage Identity and Function","volume":"52","author":"Chakarov","year":"2020","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jablonski, K.A., Amici, S.A., Webb, L.M., Ruiz-Rosado, J.D.D., Popovich, P.G., Partida-Sanchez, S., and Guerau-de-Arellano, M. (2015). Novel Markers to Delineate Murine M1 and M2 Macrophages. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145342"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1083\/jcb.144.4.789","article-title":"LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-Specific Receptor for Hyaluronan","volume":"144","author":"Banerji","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev.cellbio.23.090506.123337","article-title":"Hyaluronan in Tissue Injury and Repair","volume":"23","author":"Jiang","year":"2007","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s12026-014-8495-2","article-title":"Tissue Integrity Signals Communicated by High-Molecular Weight Hyaluronan and the Resolution of Inflammation","volume":"58","author":"Ruppert","year":"2014","journal-title":"Immunol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1002\/jbm.a.34704","article-title":"Different Molecular Weight Hyaluronic Acid Effects on Human Macrophage Interleukin 1\u03b2 Production: Effects of Lmw+Ha on Human Monocytes","volume":"102","author":"Baeva","year":"2014","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cyphert, J.M., Trempus, C.S., and Garantziotis, S. (2015). Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology. Int. J. Cell Biol., 2015.","DOI":"10.1155\/2015\/563818"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1159\/000530280","article-title":"Low-Molecular-Weight Hyaluronic Acid Contributes to Noise-Induced Cochlear Inflammation","volume":"28","author":"Zhang","year":"2023","journal-title":"Audiol. Neurootol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eabf7777","DOI":"10.1126\/sciimmunol.abf7777","article-title":"Three Tissue Resident Macrophage Subsets Coexist across Organs with Conserved Origins and Life Cycles","volume":"7","author":"Dick","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e57438","DOI":"10.7554\/eLife.57438","article-title":"Tissue-Resident Macrophages Promote Extracellular Matrix Homeostasis in the Mammary Gland Stroma of Nulliparous Mice","volume":"9","author":"Wang","year":"2020","journal-title":"eLife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1016\/j.devcel.2023.06.006","article-title":"LYVE-1+ Macrophages Form a Collaborative CCR5-Dependent Perivascular Niche That Influences Chemotherapy Responses in Murine Breast Cancer","volume":"58","author":"Anstee","year":"2023","journal-title":"Dev. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e171359","DOI":"10.1172\/jci.insight.171359","article-title":"Single-Cell Profiling Reveals Inflammatory Polarization of Human Carotid versus Femoral Plaque Leukocytes","volume":"8","author":"Slysz","year":"2023","journal-title":"JCI Insight"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41419-021-03423-2","article-title":"Inhibition of MPGES-1 Attenuates Efficient Resolution of Acute Inflammation by Enhancing CX3CL1 Expression","volume":"12","author":"Rappl","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103682","DOI":"10.18632\/oncotarget.21771","article-title":"The Shedded Ectodomain of Lyve-1 Expressed on M2-like Tumor-Associated Macrophages Inhibits Melanoma Cell Proliferation","volume":"8","author":"Dollt","year":"2017","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1083\/jcb.122.1.257","article-title":"Identification of Hyaluronic Acid Binding Sites in the Extracellular Domain of CD44","volume":"122","author":"Peach","year":"1993","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1084\/jem.183.5.2373","article-title":"Hyaluronan Fragments Activate an NF-Kappa B\/I-Kappa B Alpha Autoregulatory Loop in Murine Macrophages","volume":"183","author":"Noble","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1165\/rcmb.2010-0387OC","article-title":"Hyaluronan Fragments Promote Inflammation by Down-Regulating the Anti-Inflammatory A2a Receptor","volume":"45","author":"Collins","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Shi, Q., Zhao, L., Xu, C., Zhang, L., and Zhao, H. (2019). High Molecular Weight Hyaluronan Suppresses Macrophage M1 Polarization and Enhances IL-10 Production in PM2.5-Induced Lung Inflammation. Molecules, 24.","DOI":"10.3390\/molecules24091766"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8414","DOI":"10.1523\/JNEUROSCI.1189-21.2021","article-title":"PI3K\u03b3\/AKT Signaling in High Molecular Weight Hyaluronan (HMWH)-Induced Anti-Hyperalgesia and Reversal of Nociceptor Sensitization","volume":"41","author":"Bonet","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage Plasticity, Polarization, and Function in Health and Disease","volume":"233","author":"Mohammadian","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.immuni.2014.01.006","article-title":"Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation","volume":"40","author":"Xue","year":"2014","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41590-019-0356-7","article-title":"Dynamic Changes to Lipid Mediators Support Transitions among Macrophage Subtypes during Muscle Regeneration","volume":"20","author":"Giannakis","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e2114739119","DOI":"10.1073\/pnas.2114739119","article-title":"Triglyceride Breakdown from Lipid Droplets Regulates the Inflammatory Response in Macrophages","volume":"119","author":"Vrieling","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"565","DOI":"10.4049\/jimmunol.1202462","article-title":"PGE2 Induces Macrophage IL-10 Production and a Regulatory-like Phenotype via a Protein Kinase A\u2013SIK\u2013CRTC3 Pathway","volume":"190","author":"MacKenzie","year":"2013","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s00281-012-0342-8","article-title":"Multifaceted Roles of PGE2 in Inflammation and Cancer","volume":"35","author":"Nakanishi","year":"2013","journal-title":"Semin. Immunopathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4049\/jimmunol.1101029","article-title":"Regulation of Immune Responses by Prostaglandin E2","volume":"188","author":"Kalinski","year":"2012","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1172\/JCI119054","article-title":"Hyaluronan (HA) Fragments Induce Chemokine Gene Expression in Alveolar Macrophages. The Role of HA Size and CD44","volume":"98","author":"McKee","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fimmu.2014.00101","article-title":"Hyaluronan, a Crucial Regulator of Inflammation","volume":"5","author":"Petrey","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8013","DOI":"10.1074\/jbc.272.12.8013","article-title":"Hyaluronan Fragments Induce Nitric-Oxide Synthase in Murine Macrophages through a Nuclear Factor \u039aB-Dependent Mechanism","volume":"272","author":"McKee","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1093\/glycob\/cwn109","article-title":"Hyaluronan Receptors Involved in Cytokine Induction in Monocytes","volume":"19","author":"Yamawaki","year":"2008","journal-title":"Glycobiology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1152\/physrev.00052.2009","article-title":"Hyaluronan as an Immune Regulator in Human Diseases","volume":"91","author":"Jiang","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1038\/s41591-020-0939-8","article-title":"Distinct Synovial Tissue Macrophage Subsets Regulate Inflammation and Remission in Rheumatoid Arthritis","volume":"26","author":"Alivernini","year":"2020","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5176","DOI":"10.1038\/s41598-022-08987-3","article-title":"Kinetics of LYVE-1-Positive M2-like Macrophages in Developing and Repairing Dental Pulp in Vivo and Their pro-Angiogenic Activity in Vitro","volume":"12","author":"Kieu","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1128\/IAI.00949-09","article-title":"CD44 Deficiency Is Associated with Enhanced Escherichia Coli -Induced Proinflammatory Cytokine and Chemokine Release by Peritoneal Macrophages","volume":"78","author":"Florquin","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"758","DOI":"10.4049\/jimmunol.1700713","article-title":"Role of CD44 in Regulating TLR2 Activation of Human Macrophages and Downstream Expression of Proinflammatory Cytokines","volume":"200","author":"Qadri","year":"2018","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Johnson, L.A., and Jackson, D.G. (2021). Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System. 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