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However, how this process is controlled to maintain homeostasis and resolve inflammation is unclear. Here, we show that MARCO is a decoy LPS sensor crucial for restraining caspase 11 activity and the non-canonical inflammasome. Remarkably, MARCO expression is controlled by a non-canonical TLR signaling pathway involving the metabolite itaconate, the autophagy adaptor protein p62, and the transcription factor NRF2. In the presence of IFN, non-canonical TLR signaling is impaired and NRF2 dependent gene expression is terminated. Thus, impairing MARCO expression and licensing optimal activation of the non-canonical inflammasome. Loss of MARCO augments non-canonical inflammasome activation and sensitizes mice to septic shock. Together, this study identifies MARCO as a previously unknown LPS sensor that is regulated by a non-canonical TLR signaling pathway and reveals an intricate homeostatic switch that allows for optimal immune responses and resolution of inflammation.<\/jats:p>","DOI":"10.1101\/2025.03.10.642106","type":"posted-content","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T23:20:27Z","timestamp":1741908027000},"source":"Crossref","is-referenced-by-count":0,"title":["Non-canonical TLR signaling restricts cytosolic LPS detection"],"prefix":"10.64898","author":[{"given":"Shriram","family":"Ramani","sequence":"first","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cahill","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Finnegan","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurel","family":"Stine","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Sondrini","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiera","family":"Clayton","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liraz","family":"Shmeul-Galia","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Centre, Dallas, Texas, USA"},{"name":"Department of Immunology, University of Texas Southwestern Medical Centre, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0216-5776","authenticated-orcid":false,"given":"Fiachra","family":"Humphries","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071510501281000_2025.03.10.642106v2.1","doi-asserted-by":"crossref","unstructured":"Vijay A. 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