{"doi":"10.1088/1741-2552/ad6596","title":"Delayed administration of interleukin-4 coacervate alleviates the neurotoxic phenotype of astrocytes and promotes functional recovery after a contusion spinal cord injury","abstract":"Abstract Objective . Macrophages and astrocytes play a crucial role in the aftermath of a traumatic spinal cord injury (SCI). Infiltrating macrophages adopt a pro-inflammatory phenotype while resident astrocytes adopt a neurotoxic phenotype at the injury site, both of which contribute to neuronal death and inhibit axonal regeneration. The cytokine interleukin-4 (IL-4) has shown significant promise in preclinical models of SCI by alleviating the macrophage-mediated inflammation and promoting functional recovery. However, its effect on neurotoxic reactive astrocytes remains to be elucidated, which we explored in this study. We also studied the beneficial effects of a sustained release of IL-4 from an injectable biomaterial compared to bolus administration of IL-4. Approach . We fabricated a heparin-based coacervate capable of anchoring and releasing bioactive IL-4 and tested its efficacy in vitro and in vivo. Main results . We show that IL-4 coacervate is biocompatible and drives a robust anti-inflammatory macrophage phenotype in culture. We also show that IL-4 and IL-4 coacervate can alleviate the reactive neurotoxic phenotype of astrocytes in culture. Finally, using a murine model of contusion SCI, we show that IL-4 and IL-4 coacervate, injected intraspinally 2 d post-injury, can reduce macrophage-mediated inflammation, and alleviate neurotoxic astrocyte phenotype, acutely and chronically, while also promoting neuroprotection with significant improvements in hindlimb locomotor recovery. We observed that IL-4 coacervate can promote a more robust regenerative macrophage phenotype in vitro , as well as match its efficacy in vivo, compared to bolus IL-4. Significance . Our work shows the promise of coacervate as a great choice for local and prolonged delivery of cytokines like IL-4. We support this by showing that the coacervate can release bioactive IL-4, which acts on macrophages and astrocytes to promote a pro-regenerative environment following a SCI leading to robust neuroprotective and functional outcomes.","journal":"Journal of Neural Engineering","year":2024,"id":468631,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":420629,"name":"Anthony R. D’Amato","orcid":"0000-0002-8866-4180","position":1,"is_corresponding":false},{"id":1120309,"name":"Jayant Saksena","orcid":null,"position":2,"is_corresponding":false},{"id":320186,"name":"Phillip G. Popovich","orcid":"0000-0003-1329-7395","position":3,"is_corresponding":false},{"id":276016,"name":"Yadong Wang","orcid":"0000-0003-2067-382X","position":4,"is_corresponding":false},{"id":329692,"name":"Ryan J. Gilbert","orcid":"0000-0002-3501-6753","position":5,"is_corresponding":false},{"id":354527,"name":"Manoj K. Gottipati","orcid":"0000-0002-6998-4904","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T02:05:23.500722Z","pmid":"39029499","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":[]}