An unconventional mechanism of IL-1β secretion that requires Type I IFN in lupus monocytes.

TitleAn unconventional mechanism of IL-1β secretion that requires Type I IFN in lupus monocytes.
Publication TypeJournal Article
Year of Publication2023
AuthorsCaielli S, Balasubramanian P, Rodriguez-Alcazar J, Balaji U, Wan Z, Baisch J, Smitherman C, Walters L, Sparagana P, Nehar-Belaid D, Marches R, Nassi L, Stewart K, Fuller J, Banchereau JF, Gu J, Wright T, Pascual V
Date Published2023 Aug 03

Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN 1 . Thus, defective removal of mitochondria from mature red blood cells (Mito + RBCs), a feature of SLE, contributes to IFN production by myeloid cells 2 . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1β (IL-1β) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito + RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1β production entails Mito + RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1β release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.

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Alternate JournalbioRxiv
PubMed ID37577613
PubMed Central IDPMC10418156

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