{"doi":"10.1002/jlb.3a0218-069rr","title":"IRF3 inhibits IFN-γ-mediated restriction of intracellular pathogens in macrophages independently of IFNAR","abstract":"Macrophages use an array of innate immune sensors to detect intracellular pathogens and to tailor effective antimicrobial responses. In addition, extrinsic activation with the cytokine IFN-γ is often required as well to tip the scales of the host-pathogen balance toward pathogen restriction. However, little is known about how host-pathogen sensing impacts the antimicrobial IFN-γ-activated state. It was observed that in the absence of IRF3, a key downstream component of pathogen sensing pathways, IFN-γ-primed macrophages more efficiently restricted the intracellular bacterium Legionella pneumophila and the intracellular protozoan parasite Trypanosoma cruzi. This effect did not require IFNAR, the receptor for Type I IFNs known to be induced by IRF3, nor the sensing adaptors MyD88/TRIF, MAVS, or STING. This effect also did not involve differential activation of STAT1, the major signaling protein downstream of both Type 1 and Type 2 IFN receptors. IRF3-deficient macrophages displayed a significantly altered IFN-γ-induced gene expression program, with up-regulation of microbial restriction factors such as Nos2. Finally, we found that IFN-γ-primed but not unprimed macrophages largely excluded the activated form of IRF3 from the nucleus following bacterial infection. These data are consistent with a relationship of mutual inhibition between IRF3 and IFN-γ-activated programs, possibly as a component of a partially reversible mechanism for modulating the activity of potent innate immune effectors (such as Nos2) in the context of intracellular infection.","journal":"Journal of Leukocyte Biology","year":2021,"id":184701,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":15886,"name":"Raktima Raychowdhury","orcid":null,"position":1,"is_corresponding":false},{"id":740051,"name":"Karen Smith","orcid":"0000-0003-3932-4988","position":2,"is_corresponding":false},{"id":551751,"name":"Alexis M. Schneider","orcid":"0000-0002-2158-6915","position":3,"is_corresponding":false},{"id":249863,"name":"Jörn Coers","orcid":"0000-0001-8707-4608","position":4,"is_corresponding":false},{"id":25403,"name":"Maxwell R. Mumbach","orcid":"0000-0002-5570-6663","position":5,"is_corresponding":false},{"id":25401,"name":"Schraga Schwartz","orcid":"0000-0002-3671-9709","position":6,"is_corresponding":false},{"id":409,"name":"Nir Hacohen","orcid":"0000-0002-2349-2656","position":7,"is_corresponding":false},{"id":68283,"name":"Karolina Maciag","orcid":"0000-0003-0803-4312","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-18T23:48:30.970730Z","pmid":"34826345","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":[]}