Background/Purpose: Activation of toll-like receptor 7 and 8 (TLR7/8) signaling by single-stranded RNA results in immune cell stimulation and inflammatory cytokine production, a normal circumstance in a protective antiviral host response. In autoimmune conditions such as lupus, aberrant activation of TLR7/8 can be pathogenic and contribute to disease progression. The primary cell types stimulated by TLR7/8 activation are plasmacytoid dendritic cells, B cells, neutrophils and monocytes. In this study, we aimed to determine if a highly selective TLR7/8 inhibitor (TLR7/8i) can reverse established nephritis in a mouse model of lupus.

Methods: NZB/W mice were injected intravenously on two consecutive days with an adenovirus encoding for mouse interferon-alpha (IFN-α) to accelerate and synchronize disease progression. Approximately 4 weeks after IFN-α injection, mice developed proteinuria which was measured and reported as the urine protein:creatinine ratio (UPCR). Treatment with 10 mg/kg of an enpatoran-like TLR7/8i orally once daily was started after animals showed signs of proteinuria (UPCR >3 g/g).

Results: In independent experiments, we found that therapeutic TLR7/8 inhibition lowered proteinuria values as early as 2 weeks after the initiation of treatment. Over a total treatment period of 6 weeks, the majority of mice in the TLR7/8i-treated group were rescued from proteinuria and survival was increased from 0% in the vehicle group to 90% in TLR7/8i-treated group. Conversely, daily administration of 300 mg/kg mycophenolate mofetil did not reverse proteinuria and only rescued survival in 50% of the animals. The glomerulonephritis histology score was significantly reduced after TLR7/8i treatment compared to the vehicle group. Total splenocyte numbers, plasma cells and activated T cells were all reduced, providing insight into the mechanism of action of the TLR7/8i.

Conclusion: In the IFN-α-accelerated NZB/W mouse model, TLR7/8 inhibition effectively reduced established kidney disease, suggesting that this therapeutic strategy may be useful for the treatment of patients with lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-tlr7-8-inhibitor-enpatoran-reverses-established-kidney-disease-in-the-interferon-alpha-accelerated-nzb-w-mouse-model-of-lupus/