Mechanisms linking the cell death machinery to TLR7 immunity in lupus

Inflammation provides our frontline defense against pathogens but must be carefully regulated to avoid damaging our tissues. In Systemic Lupus Erythematosus (SLE), inflammatory responses become overexuberant, triggering immune cells to misrecognize and therefore attack multiple tissues as if they were foreign pathogens. In order to therapeutically reverse these disease processes, a detailed molecular and cellular understanding is needed of how this breakdown in the regulation of inflammation initially occurs. Genetic mutations affecting a wide variety of proteins in disparate pathways have been implicated as potential causes of SLE, but whether any unifying mechanisms can explain how these distinct mutations might converge on causing SLE is unknown. For example, in rare cases, mutations in Toll-like receptor (TLR)7 cause SLE. Studies in animal models support a central role for TLR7 in SLE-like disease, but most genetic studies have implicated non-TLR7 genes in SLE. Here, we propose studying a novel hypothesis that potentially links multiple ‘non-TLR7’  SLE genetic variants with altered TLR7 immunity. This hypothesis centers around our recent discovery of an immunosuppressive protein, Nedd4-binding protein 1 (N4BP1). Notably, we found that N4BP1 restrains inflammatory responses. We will therefore test the hypothesis that multiple SLE-associated gene variants alter the regulation of TLR7 through their effects on N4BP1. If successful, our proposal will shed light on fundamental disease mechanisms and nominate a new pathway as a potential therapeutic target in SLE caused by specific genetic variants. 

Toll-like receptor (TLR)7 senses endosomal single-stranded (ss)RNA and is a major mediator of Systemic Lupus Erythematosus (SLE) pathogenesis. For example, Tlr7 contributes to SLE pathogenesis across multiple animal models, and human mutations in TLR7 are a monogenic cause of SLE. While the MyD88-dependent pathway of TLR7 signaling has been extensively studied, signaling mechanisms that modulate these pathways and integrate TLR7 signaling with other inflammatory signals remain poorly understood. Recently, we discovered that multiple immune signals, including TNF, FASL, and the TRIF-dependent toll-like receptors (TLRs) 3 and 4, activate the protease Caspase-8 and induce cleavage and inactivation of the immunosuppressive protein, N4BP1. These findings led us to propose a model in which N4BP1 acts as a key point of signal integration during inflammation, wherein caspase-8 cleavage of N4BP1 ‘licenses’ hyperinflammatory responses by immune cells that simultaneously receive signals through both caspase-8activating receptors (e.g., TNFR1, FAS, and the TRIF-dependent TLRs) and non-caspase-8-activating receptors (e.g., TLR7) We hypothesize that variants in genes associate with SLE will alter this Caspase-8-N4BP1 axis and thereby contribute to SLE pathogenesis by augmenting TLR7-mediated inflammation.