{"doi":"10.3390/cells14191507","title":"MyD88 Contributes to TLR3-Mediated NF-κB Activation and Cytokine Production in Macrophages","abstract":"Toll-like receptor 3 (TLR3) initiates antiviral and inflammatory responses exclusively through the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β). In contrast, MyD88 (myeloid differentiation primary response 88), a central adaptor for most other TLRs, is traditionally considered dispensable for TLR3 signaling. Here, we demonstrate that MyD88 directly contributes to TLR3-mediated NF-κB activation and cytokine production in macrophages. Bone marrow-derived macrophages (BMDMs) from MyD88 deficient mice exhibited significantly attenuated NF-κB activation in response to the TLR3 agonist polyinosinic-polycytidylic acid (poly(I:C)) compared to wild-type cells, as evidenced by the reduced phosphorylation of NF-κB p65 and IκBα, as well as IκBα degradation. Consistently, pro-inflammatory cytokine production, including IL-6, TNF-α, and IFN-β, was attenuated in MyD88-deficient BMDMs in vitro following stimulation by poly(I:C) or poly(A:U), another TLR3 agonist. Blood concentrations of IL-6, TNF-α, and IFN-β were significantly reduced in both TRIF-deficient mice and MyD88-deficient mice challenged by the i.p. injection of poly(I:C). Mechanistic analyses revealed that MyD88 physically associates with activated TLR3 upon poly(I:C) stimulation, and that TLR3 engagement triggered MyD88 oligomerization, which was absent in TLR3 or TRIF deficient macrophages. Our findings highlight a previously unrecognized dual-adaptor mechanism for TLR3, wherein MyD88 recruitment amplifies NF-κB signaling dynamics by bridging TLR3 to the canonical NF-κB activation cascade and robust cytokine induction. This study expands the paradigm of TLR3 signaling by establishing MyD88 as a direct contributor to TLR3-driven innate immune responses, offering new insight into cross-talk between MyD88-dependent and -independent pathways.","journal":"Cells","year":2025,"id":513585,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"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":487253,"name":"Yuqi Zhou","orcid":"0009-0009-5656-8475","position":1,"is_corresponding":false},{"id":632851,"name":"Ling Yang","orcid":"0009-0006-3974-6100","position":2,"is_corresponding":false},{"id":376695,"name":"Yan Zhang","orcid":"0000-0003-0472-3399","position":3,"is_corresponding":false},{"id":1372444,"name":"Sukria Hossain","orcid":null,"position":4,"is_corresponding":false},{"id":1209356,"name":"Sahelosadat Hajimirzaei","orcid":null,"position":5,"is_corresponding":false},{"id":1371761,"name":"Jiaqian Qi","orcid":"0000-0002-1613-4877","position":6,"is_corresponding":false},{"id":574963,"name":"Guoying Zhang","orcid":"0000-0001-9568-3702","position":7,"is_corresponding":false},{"id":517379,"name":"Yinan Wei","orcid":"0000-0002-9936-7149","position":8,"is_corresponding":false},{"id":695637,"name":"Zhenyu Li","orcid":"0000-0002-3850-7451","position":9,"is_corresponding":false},{"id":1367453,"name":"Zhuodong Chai","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:48:17.908238Z","pmid":"41090736","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":[]}