# Innate immune responses to lysosomal nucleic acid stress

## TL;DR

Lysosomal nucleic acid stress triggers innate immune responses, which can protect against infections but also cause diseases like autoinflammation and histiocytic disorders.

## Contribution

The paper introduces the concept of lysosomal nucleic acid stress as a key environmental signal in innate immunity.

## Key findings

- Lysosomal nucleic acid stress activates TLR8 in macrophages, leading to histiocytic diseases.
- DNase II deficiency causes lysosomal DNA stress, activating cGAS-STING and AIM2 to drive autoinflammatory diseases.
- Lysosomal nucleic acid stress is a dual-edged signal for both host defense and disease progression.

## Abstract

Nucleic acids (NAs) are recognized by endosomal Toll-like receptors (TLRs) and cytoplasmic sensors in innate immune cells. NAs accumulate within lysosomes due to either excessive NA influx or defective lysosomal degradation. The resultant storage of NAs and/or NA metabolites in the lysosome, referred to here as lysosomal NA stress, elicits a spectrum of responses, ranging from inflammation to tissue repair, through NA sensor activation. Although these responses contribute to host defence against infection, they may also drive diseases. For instance, loss of function of the lysosomal nucleoside transporter SLC29A3 drives lysosomal nucleoside stress, which activates TLR8 in macrophages to cause histiocytic diseases collectively called SLC29A3 disorders. Similarly, DNase II deficiency promotes lysosomal DNA stress, leading to activation of cytoplasmic double-stranded DNA sensors, such as cGAS-STING and AIM2, and thereby autoinflammatory and autoimmune diseases. Thus, lysosomal NA stress is viewed as a pivotal environmental signal that initiates innate immune responses.

Graphical Abstract