{"doi":"10.1101/2025.05.15.654340","title":"Chromatin Remodeling and Transcriptional Silencing Define the Dynamic Innate Immune Response of Tissue Resident Macrophages After Burn Injury","abstract":"Summary Severe burn injury induces long-lasting immune dysfunction, but the molecular mechanisms underlying this phenomenon remain unclear. We hypothesized that burn injury leads to epigenetic and transcriptional reprogramming of innate immune cells. Splenic F4/80⁺ macrophages were isolated from mice at days 2, 9, and 14 days post-20% contact burn injury. Targeted transcriptomics and MAPit single-molecule chromatin profiling were used to assess immune, metabolic, and epigenetic changes. Canonical pathway analysis was performed to infer functional shifts over time. Burn injury induced a biphasic response in macrophages. Early after injury (Day 2), there was broad transcriptional suppression and epigenetic silencing of inflammatory regulators, including Stat3 , Traf6 , and Nfkb1 . Over time (Days 9 and 14), loci associated with anti-inflammatory mediators such as Il-10 and Socs3 exhibited progressive chromatin opening and transcriptional upregulation. Metabolic gene profiles revealed persistent suppression of mitochondrial and oxidative phosphorylation programs. Canonical pathway analysis demonstrated early IL-10 signaling activation with sustained suppression of classical macrophage activation pathways. Chromatin architecture changes included nucleosome sliding and ejection events, consistent with dynamic, locus-specific regulation. This work challenges the classical notion of burn-induced immune suppression as purely a consequence of systemic inflammation. Instead, we reveal a programmed and locus-specific epigenetic architecture that may shape macrophage immune and metabolic function long after the acute phase.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566383,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9651,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":258271,"name":"Marie‐Pierre L. Gauthier","orcid":"0009-0002-1936-2231","position":1,"is_corresponding":false},{"id":1470129,"name":"Aidan Higgs","orcid":"0000-0003-1602-3381","position":2,"is_corresponding":false},{"id":1320886,"name":"Denise A. Hernandez","orcid":"0009-0005-3775-4441","position":3,"is_corresponding":false},{"id":989495,"name":"Mingqi Zhou","orcid":"0000-0002-4605-5467","position":4,"is_corresponding":false},{"id":989498,"name":"Jason O. Brant","orcid":"0000-0002-9800-9251","position":5,"is_corresponding":false},{"id":86476,"name":"Rhonda Bacher","orcid":"0000-0001-5787-476X","position":6,"is_corresponding":false},{"id":376603,"name":"Dijoia B. Darden","orcid":"0000-0001-6022-1014","position":7,"is_corresponding":false},{"id":551792,"name":"Shannon M. Wallet","orcid":"0000-0003-4650-651X","position":8,"is_corresponding":false},{"id":389036,"name":"Clayton E. Mathews","orcid":"0000-0002-8817-6355","position":9,"is_corresponding":false},{"id":376602,"name":"Philip A. Efron","orcid":"0000-0002-3931-650X","position":10,"is_corresponding":false},{"id":447551,"name":"Michael P. Kladde","orcid":"0000-0001-7951-9291","position":11,"is_corresponding":false},{"id":551791,"name":"Robert Maile","orcid":"0000-0002-9126-4188","position":12,"is_corresponding":false},{"id":106387,"name":"Han Sang Kim","orcid":"0000-0002-6504-9927","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:56:36.440192Z","pmid":"40475502","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":[]}