{"doi":"10.1002/jlb.3a0820-207r","title":"Neutrophil recruitment by chemokines Cxcl1/KC and Cxcl2/MIP2: Role of Cxcr2 activation and glycosaminoglycan interactions","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Chemokines play a crucial role in combating microbial infection by recruiting blood neutrophils to infected tissue. In mice, the chemokines Cxcl1/KC and Cxcl2/MIP2 fulfill this role. Cxcl1 and Cxcl2 exist as monomers and dimers, and exert their function by activating the Cxcr2 receptor and binding glycosaminoglycans (GAGs). Here, we characterized Cxcr2 G protein and β-arrestin activities, and GAG heparan sulfate (HS) interactions of Cxcl1 and Cxcl2 and of the trapped dimeric variants. To understand how Cxcr2 and GAG interactions impact in vivo function, we characterized their neutrophil recruitment activity to the peritoneum, Cxcr2 and CD11b levels on peritoneal and blood neutrophils, and transport profiles out of the peritoneum. Cxcl2 variants compared with Cxcl1 variants were more potent for Cxcr2 activity. Native Cxcl1 compared with native Cxcl2 and dimers compared with native proteins bound HS with higher affinity. Interestingly, recruitment activity between native Cxcl1 and Cxcl2, between dimers, and between the native protein and the dimer could be similar or very different depending on the dose or the time point. These data indicate that peritoneal neutrophil recruitment cannot be solely attributed to Cxcr2 or GAG interactions, and that the relationship between recruited neutrophils, Cxcr2 activation, GAG interactions, and chemokine levels is complex and highly context dependent. We propose that the ability of Cxcl1 and Cxcl2 to reversibly exist as monomers and dimers and differences in their Cxcr2 activity and GAG interactions coordinate neutrophil recruitment and activation, which play a critical role for successful resolution of inflammation.</jats:p>","journal":"Journal of Leukocyte Biology","year":2021,"id":645223,"datarank":0.7612760722850741,"base_score":5.075173815233827,"endowment":5.075173815233827,"self_citation_contribution":0.7612760722850741,"citation_network_contribution":0.0,"self_endowment_contribution":0.7612760722850741,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":159,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":18,"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":390823,"name":"Krishna Mohan Sepuru","orcid":"0000-0002-3675-6294","position":1,"is_corresponding":false},{"id":638117,"name":"Emily Lowry","orcid":"0000-0003-1036-779X","position":2,"is_corresponding":false},{"id":1060078,"name":"Brigith Penaranda","orcid":null,"position":3,"is_corresponding":false},{"id":1679940,"name":"Charles W Frevert","orcid":null,"position":4,"is_corresponding":false},{"id":1500716,"name":"Roberto P Garofalo","orcid":null,"position":5,"is_corresponding":false},{"id":390826,"name":"Krishna Rajarathnam","orcid":"0000-0002-0077-700X","position":6,"is_corresponding":false},{"id":1679939,"name":"Kirti V Sawant","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Neutrophil recruitment by chemokines Cxcl1/KC and Cxcl2/MIP2: Role of Cxcr2 activation and glycosaminoglycan interactions","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>Chemokines play a crucial role in combating microbial infection by recruiting blood neutrophils to infected tissue. In mice, the chemokines Cxcl1/KC and Cxcl2/MIP2 fulfill this role. Cxcl1 and Cxcl2 exist as monomers and dimers, and exert their function by activating the Cxcr2 receptor and binding glycosaminoglycans (GAGs). Here, we characterized Cxcr2 G protein and β-arrestin activities, and GAG heparan sulfate (HS) interactions of Cxcl1 and Cxcl2 and of the trapped dimeric variants. To understand how Cxcr2 and GAG interactions impact in vivo function, we characterized their neutrophil recruitment activity to the peritoneum, Cxcr2 and CD11b levels on peritoneal and blood neutrophils, and transport profiles out of the peritoneum. Cxcl2 variants compared with Cxcl1 variants were more potent for Cxcr2 activity. Native Cxcl1 compared with native Cxcl2 and dimers compared with native proteins bound HS with higher affinity. Interestingly, recruitment activity between native Cxcl1 and Cxcl2, between dimers, and between the native protein and the dimer could be similar or very different depending on the dose or the time point. These data indicate that peritoneal neutrophil recruitment cannot be solely attributed to Cxcr2 or GAG interactions, and that the relationship between recruited neutrophils, Cxcr2 activation, GAG interactions, and chemokine levels is complex and highly context dependent. We propose that the ability of Cxcl1 and Cxcl2 to reversibly exist as monomers and dimers and differences in their Cxcr2 activity and GAG interactions coordinate neutrophil recruitment and activation, which play a critical role for successful resolution of inflammation.</jats:p>","is_dataset_classified":null,"base_score":5.075173815233827,"endowment":5.075173815233827,"datacite_reuse_total":18,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"32881070","pmcid":"PMC8296306","openalex_id":"https://openalex.org/W3082526716","authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"R21 AI124681","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"P30 DK017047","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI130280","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R01 AI136468","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R21 AI135606","title":null}],"total_grants":5,"fwci":4.015,"citation_percentile":0.9517601,"influential_citations":0,"citation_trend":[{"year":2021,"count":21},{"year":2022,"count":12},{"year":2023,"count":23},{"year":2024,"count":45},{"year":2025,"count":34},{"year":2026,"count":23}],"oa_status":"green","license":"http://doi.wiley.com/10.1002/tdm_license_1.1","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8296306","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8296306","host_type":"repository"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/JLB.3A0820-207R","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/JLB.3A0820-207R","host_type":"publisher"},{"url":"https://academic.oup.com/jleukbio/article-pdf/109/4/777/49461016/jlb10797.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1002/jlb.3a0820-207r","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/32881070","host_type":"repository"}],"fields_of_study":["Immune Response and Inflammation","Chemokine receptors and signaling","Cell Adhesion Molecules Research","Amino Acid Sequence","Animals","Bone Marrow Cells","CD11b Antigen","Chemokine CXCL1","Chemokine CXCL2","Female","Glycosaminoglycans","Kinetics","Mice, Inbred BALB C","Neutrophil Infiltration","Peritoneum","Protein Binding","Protein Multimerization","Protein Transport","Receptors, Interleukin-8B","Mice"],"mesh_terms":["Amino Acid Sequence","Animals","Bone Marrow Cells","Female","Glycosaminoglycans","Kinetics","Mice, Inbred BALB C","Peritoneum","Protein Binding","Neutrophil Infiltration","Protein Transport","Receptors, Interleukin-8B","CD11b Antigen","Mice","Chemokine CXCL1","Chemokine CXCL2","Protein Multimerization"],"keywords":["CXCL2","CXCL1","CXC chemokine receptors","Chemokine","Biology","Cell biology","Immunology","Chemokine receptor","Inflammation","Leukocyte","proteoglycan","Gpcr","Monomer-dimer"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.25200606.v1","title":"Additional file 1 of NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow–retina crosstalk","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25200606","title":"Additional file 1 of NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow–retina crosstalk","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26678897.v1","title":"Additional file 4 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678897","title":"Additional file 4 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678891","title":"Additional file 2 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678888","title":"Additional file 1 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678894.v1","title":"Additional file 3 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678891.v1","title":"Additional file 2 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678894","title":"Additional file 3 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.26678888.v1","title":"Additional file 1 of Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623087.v1","title":"Additional file 4 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623087","title":"Additional file 4 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623078.v1","title":"Additional file 1 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623084","title":"Additional file 3 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623081","title":"Additional file 2 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623081.v1","title":"Additional file 2 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623084.v1","title":"Additional file 3 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"},{"doi":"10.6084/m9.figshare.14623078","title":"Additional file 1 of GSDMD contributes to host defence against Staphylococcus aureus skin infection by suppressing the Cxcl1–Cxcr2 axis","publisher":"figshare","resource_type":"Image"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T03:47:07.782561Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}