Regulation of type I interferon responses by mitochondria-derived reactive oxygen species in plasmacytoid dendritic cells

Abstract

Mitochondrial reactive oxygen species (mtROS) generated continuously under physiological conditions have recently emerged as critical players in the regulation of immune signaling pathways. In this study we have investigated the regulation of antiviral signaling by increased mtROS production in plasmacytoid dendritic cells (pDCs), which, as major producers of type I interferons (IFN), are the key coordinators of antiviral immunity. The early phase of type I IFN production in pDCs is mediated by endosomal Toll-like receptors (TLRs), whereas the late phase of IFN response can also be triggered by cytosolic retinoic acid-inducible gene-I (RIG-I), expression of which is induced upon TLR stimulation. Therefore, pDCs provide an ideal model to study the impact of elevated mtROS on the antiviral signaling pathways initiated by receptors with distinct subcellular localization. We found that elevated level of mtROS alone did not change the phenotype and the baseline cytokine profile of resting pDCs. Nevertheless increased mtROS levels in pDCs lowered the TLR9-induced secretion of pro-inflammatory mediators slightly, whereas reduced type I IFN production markedly via blocking phosphorylation of interferon regulatory factor 7 (IRF7), the key transcription factor of the TLR9 signaling pathway. The TLR9-induced expression of RIG-I in pDCs was also negatively regulated by enhanced mtROS production. On the contrary, elevated mtROS significantly augmented the RIG-I-stimulated expression of type I IFNs, as well as the expression of mitochondrial antiviral-signaling (MAVS) protein and the phosphorylation of Akt and IRF3 that are essential components of RIG-I signaling. Collectively, our data suggest that increased mtROS exert diverse immunoregulatory functions in pDCs both in the early and late phase of type I IFN responses depending on which type of viral sensing pathway is stimulated.

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

“…These results suggest that the dynamic regulation of ROS production, likely through the modulation of complex III, may act as a rheostat that regulates the magnitude of antiviral immune responses. Consistent with these findings, Agod et al found that mitochondrial superoxide drives increased MAVS protein expression in plasmacytoid DCs, increasing Akt and IRF3 activation and subsequent type I IFN production 57 . Wang et al showed shRNA knockout of SOD2 in cell lines increased viral replication and reduced antiviral responses 58 , likely a result of decreased mitochondrial H2O2 production, a known redox-sensitive activator of NF-κB and IRF signalling 47,59-61 .…”

P53 mediates lipopolysaccharide‐induced inflammation in human gingival fibroblasts

“…Various studies have demonstrated that ROS play a significant role in the inflammatory response. 36,37 ROS overproduction after LPS treatment induces secretion of cytokines, including TNF-, IL-1 , and IL-6, through the MAPK and NF-B pathways in HGFs. 8 P53 also increased the levels of these three cytokines in our study.…”

Mitochondrial Reactive Oxygen Species Contribute to Pathological Inflammation During Influenza A Virus Infection in Mice

“…Given that mtROS are highly compartmentalized and usually have biological actions within close vicinity of their production, we postulate that a negative regulatory effect of mtROS per se on cysteine 98 on TLR7 within the endosomal compartments is unlikely, due to the diffusion limited nature of ROS. However, a possible molecular mechanism for elevated type I IFN is the one proposed by Agod et al, through which mtROS suppress the phosphorylation of IRF7 in the cytosol, which is an important transcription factor for type I IFN expression by TLR7 and TLR9 signaling (1). Therefore, we envisage a complex regulation of type I IFN expression by subcellular-specific ROS, that is, endosome NOX2-derived ROS on C98 of TLR7 directly and mtROS targeting a critical downstream regulator of TLR7 function in IRF7.…”