{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:16:22Z","timestamp":1790342182623,"version":"4.1.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Council of Norway through its Centers of Excellence Funding Scheme","award":["223255\/F50"],"award-info":[{"award-number":["223255\/F50"]}]},{"name":"NTNU Discovery"},{"name":"Liaison Committee for Education, Research and Innovation in Central Norway Innovation Researcher","award":["90794301"],"award-info":[{"award-number":["90794301"]}]},{"name":"Felles Forskningsutvalg","award":["2022\/2758"],"award-info":[{"award-number":["2022\/2758"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Endosomal toll-like receptors TLR7 and TLR8 are critical sensors of microbial RNA that initiate antiviral and antibacterial immune responses through type I interferon (IFN) and proinflammatory cytokine production. While TIRAP is traditionally associated with plasma membrane TLR signaling, recent evidence suggests that it also contributes to signaling via endosomal TLRs. Here, we examined the role of TIRAP in TLR7\/8 signaling using P7-Pen, a novel SLAMF1-derived peptide that disrupts the TIRAP\u2013MyD88 interaction. In primary human monocytes and a whole blood model, P7-Pen inhibited TLR7- and TLR8-induced expression and secretion of IRF5-regulated cytokines IFN\u03b2, IL-12p40, and IL-12p70, without effect on TNF or IL-6. Mechanistically, P7-Pen blocked TIRAP recruitment to the TLR8-MyD88 complex, leading to reduced late-stage IRAK1 activation, Akt and IKK\u03b1\/\u03b2 phosphorylation, and downstream IRF5 dimerization and nuclear translocation. Inhibition of Staphylococcus aureus\u2013induced cytokine production by P7-Pen was associated with reduced bacterial phagocytosis, impairing endosomal delivery of bacterial RNA. Notably, P7-Pen failed to inhibit murine TLR7 responses, which correlated with a lack of TIRAP recruitment to MyD88 in mouse macrophages following TLR7 ligand stimulation, highlighting species-specific differences in TLR signaling mechanisms. These findings support a noncanonical role for TIRAP in regulating IRF5-dependent signaling downstream of human TLR7 and TLR8, and demonstrate that selective disruption of TIRAP recruitment by a SLAMF1-derived peptide effectively attenuates IFN\u03b2 production. This strategy may hold therapeutic potential in diseases characterized by dysregulated type I IFN responses, such as systemic lupus erythematosus and chronic infections.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf258","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T15:02:37Z","timestamp":1761750157000},"page":"3514-3528","source":"Crossref","is-referenced-by-count":4,"title":["A novel TIRAP-MyD88 inhibitor blocks TLR7- and TLR8-induced type I IFN responses"],"prefix":"10.1093","volume":"214","author":[{"given":"Kaja Elisabeth","family":"Nilsen","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rgen","family":"Stenvik","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Skjesol","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingvild Bergdal","family":"Mestvedt","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siril Skaret","family":"Bakke","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam Soledad","family":"Giambelluca","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline S","family":"Gravastrand","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirusika","family":"Elamurugan","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liv","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terje","family":"Espevik","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]},{"name":"Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital , Trondheim,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Yurchenko","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology , Trondheim,","place":["Norway"]},{"name":"Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital , 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