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. 2024 Nov 12;57(11):2497-2513.e12.
doi: 10.1016/j.immuni.2024.09.004. Epub 2024 Oct 7.

Type I IFN drives unconventional IL-1β secretion in lupus monocytes

Simone Caielli  1 , Preetha Balasubramanian  2 , Juan Rodriguez-Alcazar  2 , Uthra Balaji  2 , Lauren Robinson  3 , Zurong Wan  2 , Jeanine Baisch  2 , Cynthia Smitherman  2 , Lynnette Walters  4 , Paola Sparagana  4 , Djamel Nehar-Belaid  5 , Radu Marches  5 , Lorien Nassi  6 , Katie Stewart  6 , Julie Fuller  6 , Jacques F Banchereau  7 , Jinghua Gu  2 , Tracey Wright  6 , Virginia Pascual  8
Affiliations

Type I IFN drives unconventional IL-1β secretion in lupus monocytes

Simone Caielli et al. Immunity. .

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.

Keywords: MxA; NLRP3; inflammasome; monocytes; red blood cells; systemic lupus erythematosus; type I interferon.

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Conflict of interest statement

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.

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