1. Type I IFN drives unconventional IL-1β secretion in lupus monocytes.
- Author
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Caielli S, Balasubramanian P, Rodriguez-Alcazar J, Balaji U, Robinson L, 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, and Pascual V
- Subjects
- Humans, DNA, Mitochondrial metabolism, DNA, Mitochondrial immunology, Adaptor Proteins, Signal Transducing metabolism, Mitochondria metabolism, Inflammasomes metabolism, Inflammasomes immunology, Signal Transduction, Receptors, Immunologic metabolism, Female, DEAD Box Protein 58 metabolism, Myxovirus Resistance Proteins metabolism, Myxovirus Resistance Proteins genetics, Monocytes immunology, Monocytes metabolism, Interleukin-1beta metabolism, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic metabolism, Interferon Type I metabolism, Interferon Type I immunology, Nucleotidyltransferases metabolism
- Abstract
Opsonization of red blood cells that retain mitochondria (Mito
+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1β (mIL-1β) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1β (IL-1β) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1β secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1β into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1β and expanded in SLE patients with active disease., Competing Interests: Declaration of interests V.P. has received consulting honoraria from Sanofi, Astra Zeneca, Regeneron, and Moderna and is the recipient of a research grant from Sanofi and a contract from Astra Zeneca. J.F.B. is an employee of Immunoledge LLC. V.P. and J.F.B. receive royalties for use of Canakinumab in sJIA., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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