{"doi":"10.1002/cti2.1164","title":"Distinct macrophage phenotypes skewed by local granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To determine the presence and spatial distribution of different macrophage phenotypes, governed by granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) skewing signals, in giant cell arteritis (GCA) lesions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Temporal artery biopsies (TABs, <jats:italic>n</jats:italic> = 11) from treatment‐naive GCA patients, aorta samples from GCA‐related aneurysms (<jats:italic>n</jats:italic> = 10) and atherosclerosis (<jats:italic>n</jats:italic> = 10) were stained by immunohistochemistry targeting selected macrophage phenotypic markers, cytokines, matrix metalloproteinases (MMPs) and growth factors. <jats:italic>In vitro</jats:italic> macrophage differentiation (<jats:italic>n</jats:italic> = 10) followed by flow cytometry, Luminex assay and ELISA were performed to assess whether GM‐CSF and M‐CSF are drivers of macrophage phenotypic heterogeneity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A distinct spatial distribution pattern of macrophage phenotypes in TABs was identified. CD206<jats:sup>+</jats:sup>/MMP‐9<jats:sup>+</jats:sup> macrophages were located at the site of tissue destruction, whereas FRβ<jats:sup>+</jats:sup> macrophages were located in the inner intima of arteries with high degrees of intimal hyperplasia. Notably, this pattern was also observed in macrophage‐rich areas in GCA aortas but not in atherosclerotic aortas. Flow cytometry showed that GM‐CSF treatment highly upregulated CD206 expression, while FRβ was expressed by M‐CSF‐skewed macrophages, only. Furthermore, localised expression of GM‐CSF and M‐CSF was detected, likely contributing to macrophage heterogeneity in the vascular wall.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our data document a distinct spatial distribution pattern of CD206<jats:sup>+</jats:sup>/MMP‐9<jats:sup>+</jats:sup> macrophages and FRβ<jats:sup>+</jats:sup> macrophages in GCA linked to tissue destruction and intimal proliferation, respectively. We suggest that these distinct macrophage phenotypes are skewed by sequential GM‐CSF and M‐CSF signals. Our study adds to a better understanding of the development and functional role of macrophage phenotypes in the pathogenesis of GCA and opens opportunities for the design of macrophage‐targeted therapies.</jats:p></jats:sec>","journal":"Clinical &amp; Translational Immunology","year":2020,"id":600217,"datarank":0.6394019815561974,"base_score":4.2626798770413155,"endowment":4.2626798770413155,"self_citation_contribution":0.6394019815561974,"citation_network_contribution":0.0,"self_endowment_contribution":0.6394019815561974,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":70,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1187611,"name":"Yannick van Sleen","orcid":"0000-0002-7382-8322","position":1,"is_corresponding":false},{"id":1538621,"name":"Kornelis SM van der Geest","orcid":null,"position":2,"is_corresponding":false},{"id":1538622,"name":"Hilde A ten Berge","orcid":null,"position":3,"is_corresponding":false},{"id":1538623,"name":"Wayel H Abdulahad","orcid":null,"position":4,"is_corresponding":false},{"id":1187612,"name":"Maria Sandovici","orcid":"0000-0002-4809-0653","position":5,"is_corresponding":false},{"id":1538624,"name":"Annemieke MH Boots","orcid":null,"position":6,"is_corresponding":false},{"id":438028,"name":"Peter Heeringa","orcid":"0000-0001-8684-763X","position":7,"is_corresponding":false},{"id":1048581,"name":"Elisabeth Brouwer","orcid":"0000-0002-5652-4423","position":8,"is_corresponding":false},{"id":1538620,"name":"William F Jiemy","orcid":"0000-0001-7712-3576","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Distinct macrophage phenotypes skewed by local granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To determine the presence and spatial distribution of different macrophage phenotypes, governed by granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) skewing signals, in giant cell arteritis (GCA) lesions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Temporal artery biopsies (TABs, <jats:italic>n</jats:italic> = 11) from treatment‐naive GCA patients, aorta samples from GCA‐related aneurysms (<jats:italic>n</jats:italic> = 10) and atherosclerosis (<jats:italic>n</jats:italic> = 10) were stained by immunohistochemistry targeting selected macrophage phenotypic markers, cytokines, matrix metalloproteinases (MMPs) and growth factors. <jats:italic>In vitro</jats:italic> macrophage differentiation (<jats:italic>n</jats:italic> = 10) followed by flow cytometry, Luminex assay and ELISA were performed to assess whether GM‐CSF and M‐CSF are drivers of macrophage phenotypic heterogeneity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A distinct spatial distribution pattern of macrophage phenotypes in TABs was identified. CD206<jats:sup>+</jats:sup>/MMP‐9<jats:sup>+</jats:sup> macrophages were located at the site of tissue destruction, whereas FRβ<jats:sup>+</jats:sup> macrophages were located in the inner intima of arteries with high degrees of intimal hyperplasia. Notably, this pattern was also observed in macrophage‐rich areas in GCA aortas but not in atherosclerotic aortas. Flow cytometry showed that GM‐CSF treatment highly upregulated CD206 expression, while FRβ was expressed by M‐CSF‐skewed macrophages, only. Furthermore, localised expression of GM‐CSF and M‐CSF was detected, likely contributing to macrophage heterogeneity in the vascular wall.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our data document a distinct spatial distribution pattern of CD206<jats:sup>+</jats:sup>/MMP‐9<jats:sup>+</jats:sup> macrophages and FRβ<jats:sup>+</jats:sup> macrophages in GCA linked to tissue destruction and intimal proliferation, respectively. We suggest that these distinct macrophage phenotypes are skewed by sequential GM‐CSF and M‐CSF signals. Our study adds to a better understanding of the development and functional role of macrophage phenotypes in the pathogenesis of GCA and opens opportunities for the design of macrophage‐targeted therapies.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":4.2626798770413155,"endowment":4.2626798770413155,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"32884747","pmcid":"PMC7453134","openalex_id":"https://openalex.org/W3081544860","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"668036","title":"RELapses prevENTion in chronic autoimmune disease: common mechanisms and co-morbidities"}],"total_grants":1,"fwci":4.0579,"citation_percentile":0.95629549,"influential_citations":0,"citation_trend":[{"year":2021,"count":7},{"year":2022,"count":17},{"year":2023,"count":13},{"year":2024,"count":12},{"year":2025,"count":13},{"year":2026,"count":7}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cti2.1164","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cti2.1164","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/cti2.1164","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cti2.1164","host_type":"publisher"},{"url":"https://doi.org/10.1002/cti2.1164","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/32884747","host_type":"repository"},{"url":"https://research.rug.nl/en/publications/f32aa343-4738-437f-adaa-32a393e68120","host_type":"repository"},{"url":"https://doaj.org/article/65049c98a25546afab7ccb4124a70405","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7453134","host_type":"repository"},{"url":"https://hdl.handle.net/11370/f32aa343-4738-437f-adaa-32a393e68120","host_type":"repository"},{"url":"https://pure.rug.nl/ws/files/133341001/Distinct_macrophage_phenotypes_skewed_by_local_granulocyte_macrophage_colony_stimulating.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC7453134","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC7453134?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.60692/q13ff-mfm68","host_type":""},{"url":"https://dx.doi.org/10.60692/a7b47-tge40","host_type":""},{"url":"http://dx.doi.org/10.1002/cti2.1164","host_type":""},{"url":"https://dx.doi.org/10.1002/cti2.1164","host_type":""}],"fields_of_study":["Vasculitis and related conditions","Atherosclerosis and Cardiovascular Diseases","Immune cells in cancer","0301 basic medicine","03 medical and health sciences","0303 health sciences"],"mesh_terms":[],"keywords":["Macrophage","Macrophage colony-stimulating factor","Granulocyte macrophage colony-stimulating factor","Pathology","Biology","M2 Macrophage","Flow cytometry","Immunology","Phenotype","Cytokine","Medicine","In vitro","Macrophages","Vasculitis","Giant Cell Arteritis","Macrophage Colony‐stimulating Factor","Granulocyte Macrophage Colony‐Stimulating Factor","EXPRESSION","Pulmonary and Respiratory Medicine","MIGRATION","Immunological Mechanisms in Atherosclerosis Development","HUMAN MONOCYTES","POLYMYALGIA-RHEUMATICA","FOLATE RECEPTOR-BETA","Biochemistry","Gene","Classification and Management of Vasculitides","Health Sciences","Integrin Signaling in Inflammation and Cancer","Immunology and Allergy","IMMUNOTOXIN","Immunology and Microbiology","INTERFERON-GAMMA","FOS: Clinical medicine","PROLIFERATION","Life Sciences","IN-VITRO","RC581-607","Original Article","ARTHRITIS","Immunologic diseases. 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