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Dysregulation of TLR9 in neonates leads to fatal inflammatory disease driven by IFN-γ

Significance Toll-like receptors (TLRs) sense and respond to foreign nucleic acids, but this specificity raises the risk of inappropriate responses to self-nucleic acids, leading to autoimmune diseases. Limiting TLR9 activation to endosomes is thought to reduce recognition of self-DNA. To test the importance of this compartmentalized activation for immune tolerance, we developed mice with inducible expression of a mutated TLR9 that bypasses the requirement for endosomal activation. While induction of expression in adults resulted in rather mild disease, expression during development resulted in neonatal fatality dependent on type II interferon (IFN) signaling and driven by macrophages and IFN-γ–producing natural killer cells. This study uses a new model to reveal unique aspects of TLR9-driven inflammatory disease, especially early in life. Recognition of self-nucleic acids by innate immune receptors can lead to the development of autoimmune and/or autoinflammatory diseases. Elucidating mechanisms associated with dysregulated activation of specific receptors may identify new disease correlates and enable more effective therapies. Here we describe an aggressive in vivo model of Toll-like receptor (TLR) 9 dysregulation, based on bypassing the compartmentalized activation of TLR9 in endosomes, and use it to uncover unique aspects of TLR9-driven disease. By inducing TLR9 dysregulation at different stages of life, we show that while dysregulation in adult mice causes a mild systemic autoinflammatory disease, dysregulation of TLR9 early in life drives a severe inflammatory disease resulting in neonatal fatality. The neonatal disease includes some hallmarks of macrophage activation syndrome but is much more severe than previously described models. Unlike TLR7-mediated disease, which requires type I interferon (IFN) receptor signaling, TLR9-driven fatality is dependent on IFN-γ receptor signaling. NK cells are likely key sources of IFN-γ in this model. We identify populations of macrophages and Ly6Chi monocytes in neonates that express high levels of TLR9 and low levels of TLR7, which may explain why TLR9 dysregulation is particularly consequential early in life, while symptoms of TLR7 dysregulation take longer to manifest. Overall, this study demonstrates that inappropriate TLR9 responses can drive a severe autoinflammatory disease under homeostatic conditions and highlights differences in the diseases resulting from inappropriate activation of TLR9 and TLR7.