Type I IFN drives unconventional IL-1β secretion in lupus monocytes.
Document Type
Article
Publication Date
11-12-2024
Original Citation
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 J,
Gu J,
Wright T,
Pascual V.
Type I IFN drives unconventional IL-1β secretion in lupus monocytes. Immunity. 2024;57(11):2497-513 e12.
Keywords
JGM, Humans, Monocytes, Interleukin-1beta, Lupus Erythematosus, Systemic, Interferon Type I, Nucleotidyltransferases, DNA, Mitochondrial, Adaptor Proteins, Signal Transducing, Mitochondria, Inflammasomes, Signal Transduction, Receptors, Immunologic, Female, DEAD Box Protein 58, Myxovirus Resistance Proteins
JAX Source
Immunity. 2024;57(11):2497-513 e12.
ISSN
1097-4180
PMID
39378884
DOI
https://doi.org/10.1016/j.immuni.2024.09.004
Abstract
Opsonization of red blood cells that retain mitochondria (Mito + RBCs), a feature of systemic lupus erythema- tosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co- produce IFN and mature interleukin-1b (mIL-1b) upon Mito + RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors’ (RLRs) sensing of Mito + RBC-derived mitochon- drial DNA (mtDNA) and mtRNA, respectively. Interleukin-1b (IL-1b) production was initiated by the RLR anti- viral 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-1b 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-1b 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-1b and expanded in SLE patients with active disease.