Type I IFN in Glomerular Disease: Scarring beyond the STING

Abstract

The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS), along with intracellular RIG-like receptors (RLRs) and toll-like receptors (TLRs), are potent inducers of type I interferon (IFN-I) expression. These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as one cause of renal disease not attributed to viral infections. Instead, this pathway can recognize and signal in response to host-derived nucleic acids, which are also recognized by RLRs and TLRs. It is still unclear, however, whether the development of renal diseases depends on subsequent IFN-I induction or other processes involved. This review aims to explore the main endogenous inducers of IFN-I in glomerular cells, to discuss what effects autocrine and paracrine signaling have on IFN-I induction, and to identify the pathways that are implicated in the development of glomerular damage.

Keywords: IFN-I pathway; STING; glomerular diseases; intracellular pattern-recognition receptors; sterile inflammation.

Figure 1

Origins and intracellular sensors of self-nucleic acids promoting the IFN-I signaling pathway. During cellular stress, self-derived nucleic acids (DNA or RNA) are released from damaged mitochondria and the nucleus, consequently accumulating in the cytosol. In addition, extracellular nucleic acids liberated from neighboring dying or damaged cells are internalized by endocytosis. These intracellular (cytosolic or endosomal) nucleic acids are recognized by diverse intracellular nucleic acid sensors, triggering the activation of the signaling pathways that produce IFN-I and proinflammatory cytokines. Specifically, sensors for endosomal nucleic acids include TLR3 (for double-stranded DNA), TLR7 (for single-stranded RNA), and TLR9 (for single-stranded DNA). Cytosolic double-stranded RNA is detected by RIG-I or MDA5, while cytosolic double-stranded DNA is recognized by members of the cGAS-STING pathway. Activation of these intracellular nucleic acid sensors stimulates TBK1 activation, prompting the translocation of IRFs and NF-kB into the nucleus. There, they orchestrate the expression of IFN-I and proinflammatory cytokine genes. Subsequently, binding of IFN-I to IFNAR1/IFNAR2 triggers the activation of the JAK-STAT pathway, culminating in the induction of ISGs. This cascade of events illustrates the intricate molecular mechanisms involved in the recognition of self-nucleic acids, the subsequent activation of signaling pathways leading to the expression and secretion of IFN-I and proinflammatory cytokines, and the subsequent induction of ISGs via the JAK-STAT pathway. This figure was created with BioRender.com. IFN-I, type I interferons; TLR, toll-like receptor; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated protein 5; cGAS, cyclic GMP-AMP (cGAMP) synthase; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; IFNAR, type I interferon receptor; ISGs, interferon-stimulated genes.

Figure 2

The potential deleterious effects of IFN-I on different glomerular cell types. IFN-I can exhibit a direct influence on diverse cell types within the glomerular compartment, altering their cellular functions. In addition, increased IFN-I levels induce the expression of interferon-stimulated genes (ISGs). This could intensify inflammatory processes by recruiting inflammatory immune cells to the kidney and increasing the production of autoantibodies. This figure was created with BioRender.com. APOL-1, apolipoprotein L1; VE-cadherin, vascular endothelial-cadherin; NO, nitric oxide. Red arrows indicate increased responses.