Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease

Abstract

Neutrophil extracellular traps (NETs) are implicated in autoimmunity but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes, inducers of NETosis, require mitochondrial ROS for maximal NET stimulation. During this process, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro and, when injected into mice, stimulates type-I interferon (IFN) signaling through a pathway dependent on the DNA sensor, STING. Mitochondrial ROS is also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus (SLE). This was also observed in individuals with chronic granulomatous disease (CGD), which lack NADPH-oxidase activity, but still develop autoimmunity and type I-IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type-I IFN responses in a mouse model of lupus. These findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.

A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22

“…This mechanism can explain the synergy between the C1858T SNP and HLA shared epitopes in ACPA + RA (56). Through hypercitrullination, this SNP also increases the propensity of the formation of NETs, which have been shown to play a pathogenic role in SLE and other autoimmune diseases (57,58). This latter mechanism satisfactorily explains the association between the C1858T SNP and a higher risk of several other autoimmune diseases (59,60), which do not have ACPA.…”

Neutrophil extracellular traps as the main source of eDNA

“…It should be assumed that the physicochemical characteristics of DNA/F-actin aggregates formed at the surface of mucosal membranes differ from that formed within tissues because assembly of negatively charged PEs is governed by local ion composition and the presence of a bundling factor (polycations), such as most cationic antibacterial peptides. Additionally the NET composition might vary based on mechanisms activating NETosis [13,18,23]. The composition of DNA-protein complexes that accumulate in airway sputum of CF patients is consistent with NETosis and joins a similar proteomic signature, indicating that the majority of the DNA in sputum is NET derived.…”

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

“…It has also been shown that mtDNA ETs from LDGs in SLE possess proinflammatory characteristics via DNA oxidation (Lood et al 2016). Thus, it is important to consider these cells in future in vitro studies on NETs.…”

“…In addition to their role as antimicrobial agents, NETs of both nuclear and mitochondrial origin have been connected to autoinflammatory or autoimmune diseases (Gupta et al 2005, Kessenbrock et al 2009, Dwivedi et al 2012, Khandpur et al 2013, Leffler et al 2013, Sur Chowdhury et al 2014, Surmiak et al 2015, Lood et al 2016, and have therefore been referred to as a double edged sword of innate immunity (Kaplan and Radic 2012).…”

“…8B) showed that the DNA in the webs was of mitochondrial origin. Although we did not investigate functional properties of these ETs more than on direct microbial cytotoxicity, oxidized mtDNA ETs released from neutrophils has been shown be proinflammatory, by inducing gene expression of TNF, IL-6 and typ I IFN in PBMCs (Lood et al 2016). mtDNA is also a well-known DAMP that can alert the immune system in a proinflammatory fashion (Nakahira et al 2015).…”