{"doi":"10.1101/2022.08.23.504963","title":"MyD88-Dependent Signaling Drives Toll-Like Receptor-Induced Trained Immunity in Macrophages","abstract":"ABSTRACT Immunocompromised populations are highly vulnerable to developing life-threatening infections. Strategies to protect patients with weak immune responses are urgently needed. Employing trained immunity, whereby innate leukocytes undergo reprogramming upon exposure to a microbial product and respond more robustly to subsequent infection, is a promising approach. Previously, we demonstrated that the TLR4 agonist monophosphoryl lipid A (MPLA) induces trained immunity and confers broad resistance to infection. TLR4 signals through both MyD88- and TRIF-dependent cascades, but the relative contribution of each pathway to induction of trained immunity is unknown. Here, we show that MPLA-induced resistance to Staphylococcus aureus infection is lost in MyD88-KO, but not TRIF-KO, mice. The MyD88-activating agonist CpG (TLR9 agonist), but not TRIF-activating Poly I:C (TLR3 agonist), protects against infection in a macrophage-dependent manner. MPLA- and CpG-induced augmentation of macrophage metabolism and antimicrobial functions is blunted in MyD88-, but not TRIF-KO, macrophages. Augmentation of antimicrobial functions occurs in parallel to metabolic reprogramming and is dependent, in part, on mTOR activation. Splenic macrophages from CpG-treated mice confirmed that TLR/MyD88-induced reprogramming occurs in vivo. TLR/MyD88-triggered metabolic and functional reprogramming was reproduced in human monocyte-derived macrophages. These data show that MyD88-dependent signaling is critical in TLR-mediated trained immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298029,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"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":275383,"name":"Liming Luan","orcid":"0000-0001-7993-4540","position":1,"is_corresponding":false},{"id":276628,"name":"Katherine R. Burelbach","orcid":null,"position":2,"is_corresponding":false},{"id":275379,"name":"Margaret A. McBride","orcid":"0000-0002-7073-7337","position":3,"is_corresponding":false},{"id":275381,"name":"Cody L. Stothers","orcid":"0000-0003-1919-9032","position":4,"is_corresponding":false},{"id":852075,"name":"Olivia A. Boykin","orcid":null,"position":5,"is_corresponding":false},{"id":851169,"name":"Kalkena Sivanesam","orcid":"0000-0002-0325-8205","position":6,"is_corresponding":false},{"id":852076,"name":"Jessica F. Schaedel","orcid":null,"position":7,"is_corresponding":false},{"id":276629,"name":"Tazeen K Patil","orcid":null,"position":8,"is_corresponding":false},{"id":851170,"name":"Jingbin Wang","orcid":"0000-0003-1321-1491","position":9,"is_corresponding":false},{"id":275382,"name":"Antonio Hernandez","orcid":"0000-0003-1651-9037","position":10,"is_corresponding":false},{"id":275385,"name":"Naeem K. Patil","orcid":"0000-0002-5323-0729","position":11,"is_corresponding":false},{"id":225202,"name":"Edward R. Sherwood","orcid":"0000-0002-9505-7178","position":12,"is_corresponding":false},{"id":275384,"name":"Julia K. Bohannon","orcid":"0000-0003-0460-9377","position":13,"is_corresponding":false},{"id":275380,"name":"Allison M. Owen","orcid":"0000-0001-5623-4891","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T00:31:31.270564Z","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":[]}