Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2 ′-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1 −/− mice showed increased influx of Ly6C hi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1 −/− mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1 −/− mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

The Third Man: DNA sensing as espionage in pulmonary vascular health and disease

“…A hallmark of connective disease, titers of auto-antibodies directed against dsDNA are known to correlate with development of PH in, especially related to scleroderma 31 and systemic lupus erythematosus (SLE) 32 . This is consistent with what is known in the DNA sensing literature, where primarily DNA-derived from mitochondria lead to increased interferon production and a worsening of lupus findings using the pristane mouse model of disease 33 . In fact, patients with the monogenic form of SLE are heavily predisposed to an amplified type 1 interferon production cycle, autoinflammatory disease and PH 34 .…”

“…Regarding translational potential of this protein, OGG1 has thus far been shown to reverse vascular barrier compromise in response to oxidant stress 46 , and hypoxia-inducible factor (HIF)-mediated endothelial cell injury 47 . OGG1 deficient mice also display an increase in auto-dsDNA antibodies in a lupus model, associated with increased interferon production and worsened objective findings of disease 33 . Ultimately, a balance must be struck between these potentially disadvantageous and beneficial mtDNA injury responses, in order to restore homeostatic cellular function.…”

“…32 This is consistent with what is known in the DNA sensing literature, where primarily DNA-derived from mitochondria lead to increased interferon production and a worsening of lupus findings using the pristane mouse model of disease. 33 In fact, patients with the monogenic form of SLE are heavily predisposed to an amplified type 1 interferon production cycle, autoinflammatory disease, and PH. 34 The link between autoantibody expression and PAH continues to be explored.…”

“…47 OGG1-deficient mice also display an increase in auto-dsDNA antibodies in a lupus model, associated with increased interferon production and worsened objective findings of disease. 33 Ultimately, a balance must be struck between these potentially disadvantageous and beneficial mtDNA injury responses, in order to restore homeostatic cellular function.…”

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

“…STING also plays a crucial role in systemic lupus erythematosus (SLE) in response to the recognition of self-DNA via LYN interaction and phosphorylation to induce conventional DC (cDC) maturation and plasmacytoid DC (pDC) differentiation ( 134 ). The oxidized mtDNA released during the process of NETosis (neutrophil extracellular traps or NETs formation) also stimulates cGAS-STING signaling during SLE that further aggravates the disease ( 20 , 135 , 136 ). The transmembrane protein 203 (TMEM203, a conserved transmembrane protein) is an intracellular regulator of STING-mediated signaling, which interacts, cooperates, and co-migrates with STING to activate TBK1 and IRF3-dependent type 1 IFNs ( 137 ).…”