IFN-I Mediates Lupus Nephritis From the Beginning to Renal Fibrosis

Abstract

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

Glomerular endothelial expression of type I IFN-stimulated gene, DExD/H-Box helicase 60 via toll-like receptor 3 signaling: possible involvement in the pathogenesis of lupus nephritis

“…Thus, regional viral and “pseudo” viral immunoreactions, including proinflammatory cytokines/chemokines production via the activation of TLR3 signaling in the intrinsic glomerular cells have been postulated to be involved in the pathogenesis of LN [ 3 , 6 , 7 , 24 ]. Furthermore, sustained activation of type I IFN is believed to participate in LN pathogenesis [ 1 , 2 ].…”

“…Sustained activation of type I interferon (IFN) has been reported to play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and the development of lupus nephritis (LN) [ 1 , 2 ]. Therefore, the involvement of innate immune system upregulation via regional Toll-like receptor (TLR) signaling, such as TLR3, TLR7, and TLR9, is believed to be involved in LN pathogenesis [ 3–7 ].…”

Lupus nephritis correlates with B cell interferon-β, anti-Smith, and anti-DNA: a retrospective study

“…Type I IFN has previously been found to mediate LN from the initial stages to the development of renal fibrosis [ 27 , 34 ]. At the initial stages, type I IFN contributes to formation of IC as well as decreased clearance of ICs [ 35 ].…”

“…At the initial stages, type I IFN contributes to formation of IC as well as decreased clearance of ICs [ 35 ]. It has been shown that renal resident cells rather than infiltrating immune cells are a main source of type I IFN [ 34 ] and can be stimulated through TLR by way of nucleic acid products including DNA and RNA-immune complexes which can induce IFNβ in renal medullary cells (RMC) [ 9 , 36 ]. Thus, IFNβ can have a dual factor of inducing IC, as well as decreasing clearance of ICs at the acute stage.…”

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

“…Based on these observations, dd-cfDNA may itself represent a danger signal that initiates an immune response in the form of dendritic cell (DC) activation. In a parallel vein, high levels of mitochondrial DNA (mtDNA) are found in the circulation of patients suffering from sepsis, trauma, and chronic organ-specific illnesses such as rheumatoid arthritis, gout, SLE, and hepatitis [ 56 , 57 , 58 , 59 ]. In transplantation, mtDNA is also released following allograft reperfusion and has also been shown to be a compelling danger signal that is recognized by the innate immune system, directly modifying the inflammatory response.…”