{"doi":"10.1172/jci.insight.156319","title":"Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage","abstract":"Circulating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and a GFP BM chimeric approach, we found neuroprotection and a lack of significant motor deficits marked by reduced monocyte/macrophage cortical infiltration and an increased number of arginase-1+ cells in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to antiinflammatory that included increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocytes/macrophages. In Epha4-BM-deficient mice, cortical-isolated GFP+ monocytes/macrophages displayed a phenotypic shift from a classical to an intermediate subtype, which displayed reduced Ly6chi concomitant with increased Ly6clo- and Tie2-expressing populations. Furthermore, clodronate liposome-mediated monocyte depletion mimicked these effects in WT mice but resulted in attenuation of phenotype in Epha4-BM-deficient mice. This demonstrates that monocyte polarization not overall recruitment dictates neural tissue damage. Thus, coordination of monocyte proinflammatory phenotypic state by Epha4 is a key regulatory step mediating brain injury.","journal":"JCI Insight","year":2022,"id":243330,"datarank":0.5333022092234121,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.0,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392990,"name":"Eman Soliman","orcid":"0000-0003-2592-7622","position":1,"is_corresponding":false},{"id":424417,"name":"Colin Kelly","orcid":"0000-0001-8129-532X","position":2,"is_corresponding":false},{"id":411747,"name":"Erwin Kristobal Gudenschwager Basso","orcid":"0000-0001-7903-9992","position":3,"is_corresponding":false},{"id":875105,"name":"John W. Leonard","orcid":"0000-0002-9052-3221","position":4,"is_corresponding":false},{"id":571549,"name":"Kevin J. Pridham","orcid":"0000-0002-2636-9688","position":5,"is_corresponding":false},{"id":672588,"name":"Jing Ju","orcid":"0000-0002-1901-6980","position":6,"is_corresponding":false},{"id":234776,"name":"Alison Cash","orcid":"0000-0001-6807-9366","position":7,"is_corresponding":false},{"id":540648,"name":"Amanda Hazy","orcid":null,"position":8,"is_corresponding":false},{"id":875106,"name":"Caroline de Jager","orcid":"0000-0003-2714-5886","position":9,"is_corresponding":false},{"id":411746,"name":"Alexandra M. Kaloss","orcid":"0000-0002-2054-2320","position":10,"is_corresponding":false},{"id":690616,"name":"Hanzhang Ding","orcid":"0000-0003-2313-9550","position":11,"is_corresponding":false},{"id":875107,"name":"Raymundo Hernandez","orcid":"0000-0001-9403-652X","position":12,"is_corresponding":false},{"id":875708,"name":"G. Coleman","orcid":null,"position":13,"is_corresponding":false},{"id":424418,"name":"Xia Wang","orcid":"0000-0002-2429-8871","position":14,"is_corresponding":false},{"id":432146,"name":"Michelle L. Olsen","orcid":"0000-0003-1394-664X","position":15,"is_corresponding":false},{"id":258695,"name":"Alicia M. Pickrell","orcid":"0000-0002-8470-6056","position":16,"is_corresponding":false},{"id":234777,"name":"Michelle H. Theus","orcid":"0000-0001-6485-2104","position":17,"is_corresponding":false},{"id":673254,"name":"Elizabeth A. Kowalski","orcid":null,"position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:23:16.032700Z","pmid":"35737458","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":[]}