Nuclear destruction is one of the main changes occurring throughout keratinocyte cornification, a differentiating-associated mode of programmed cell death. However, the mechanisms of DNA degradation during cornification remain unclear. Here, we investigated the effects in mice of simultaneous loss of the two keratinocyte-specific nucleases, the DNase1L2 endonuclease and the Trex2 exonuclease. Studies in single and double deficient mice have revealed that Trex2 and DNase1L2 contributed and cooperated in the DNA degradation process taking place during keratinocyte cornification in the tongue epithelium, whereas were dispensable for homeostatic epidermal skin cornification. Notably, simultaneous loss of Trex2 and DNase1L2 led to synergistic accumulation of DNA fragments into the uppermost lingual epithelium layers, rather than a simple sum of single DNase1l2 and Trex2 loss phenotypes, pointing out these two nucleases as essential members of the DNA degrading machinery in lingual cornification process. Intriguingly, the abnormal accumulation of cytosolic DNA in lingual corneocytes was not associated to DNA-driven immune responses and inflammation, establishing that lingual epithelium displays physiological tolerance to aberrantly retained endogenous DNA. Keratinocyte immunological tolerance to self-DNA may be explained in part by the low expression levels of key DNA sensing and signalling genes. In sum, our data indicate a keratinocyte tissue-dependent essential interplay of Trex2 and DNase1L2 in DNA degradation during homeostatic lingual cornification.

Combined loss of Trex2 and DNase1L2 nucleases leads to disrupted DNA degradation during lingual cornification and absence of inflammatory responses