TLR7 and TLR9 play very distinct roles in the development of autoimmune diseases.

GOF variants of nucleic acid sensing receptors can drive chronic sterile inflammation.

Intracellular nucleases regulate the accumulation and degradation of RNA and DNA.

Nucleic acid receptor expression in stromal cells can directly promote inflammation.

Key mechanistic insights have come from murine models of sterile inflammation.

The key role of nucleic acid sensing receptors in the development of autoimmune and autoinflammatory diseases is becoming increasingly apparent. Activation of these sensors has been attributed to the failure of professional scavenger cells to adequately clear cell debris, in many cases due to defective scavenger receptors. However, as now summarized in this review, numerous gain-of-function mutations in the nucleic acid sensing receptors, or in molecules that regulate sensor activity, have now been evaluated in gene-targeted murine strains, and critical components of their downstream pathways have been identified as therapeutic targets. In addition, we are beginning to understand how DNases and RNases play crucial roles in both generating and eliminating the distinct ligands that engage the various nucleic acid sensors. Murine models of disease have further provided important insights regarding the function of and synergy between individual endosomal and cytosolic receptors, as well as cell type restricted functions.

© 2025 The Authors. Published by Elsevier Ltd.