Extracellular DNA in immunity and autoimmunity
Extracellular DNA is continuously released during cell turnover and is normally present in circulation, yet it is tolerated by the immune system in healthy individuals. This tolerance is broken in systemic autoimmune diseases such as systemic lupus erythematosus (SLE), which feature the production of pathogenic antibodies to chromatin and/or DNA. Thus, the mechanisms of tolerance to self-DNA and its breakdown in autoimmunity represent fundamental questions of major translational significance. To address these questions, we have been studying the turnover of self-DNA and its regulation by extracellular DNases of the DNase I family. We found that DNASE1L3 digests polynucleosomal DNA in circulating microparticles released from apoptotic cells, thereby reducing immunogenicity of self-DNA. At the same time, the role of the prototypical extracellular DNase DNASE1 remains controversial, and the overall function of secreted DNases in immunity is unclear. We will discuss the latest studies on the role of extracellular DNases in autoreactivity to self-DNA, as well as immune reactivity to foreign DNA. In particular, our results suggest a role of secreted DNases in the control of bacterial infection, suggesting the original evolutionary function of these enzymes as antimicrobial agents.