An unconventional mechanism of IL-1β secretion that requires Type I IFN in lupus monocytes
Caielli, 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, J. F.; Gu, J.; Wright, T.; Pascual, V.
Show abstract
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 IFN1. Thus, defective removal of mitochondria from mature red blood cells (Mito+ RBCs), a feature of SLE, contributes to IFN production by myeloid cells2. Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1{beta} (IL-1{beta}) 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-1{beta} 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-1{beta} 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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