The Exonuclease Trex2 Shapes Psoriatic Phenotype

Abstract

Trex2 is a keratinocyte-specific 3'-deoxyribonuclease that participates in the maintenance of skin homeostasis after DNA damage. Here, we show that this exonuclease is strongly upregulated in human psoriasis, a hyperproliferative and inflammatory skin disease. Similarly, the imiquimod (IMQ)- and Il23-induced mouse psoriasis was associated with a substantial upregulation of Trex2, which was recruited into fragmented chromatin in keratinocytes that were undergoing impaired proliferation, differentiation, and cell death, indicating an important role in DNA processing. Using Trex2 knockout mice, we have found that Trex2 deficiency attenuated IMQ-induced psoriasis-like skin inflammation and enhanced IMQ-induced parakeratosis. Also, Il23-induced ear swelling was diminished in Trex2 knockout mice in comparison with wild-type (wt) mice. Transcriptome analysis identified multiple genes that were deregulated by Trex2 loss after treatment with IMQ. Specifically, immune response genes and pathways normally associated with inflammation were downregulated, whereas those related to skin differentiation and chromatin biology showed increased expression. Interestingly, Trex2 deficiency led to decreased IMQ-induced keratinocyte death via both cell autonomous and noncell autonomous mechanisms. Hence, our data indicate that Trex2 acts as a critical factor in the pathogenesis of psoriasis by promoting keratinocyte apoptosis and enucleation and thereby influencing skin immune responses.

Inactivation of DNase1L2 and DNase2 in keratinocytes suppresses DNA degradation during epidermal cornification and results in constitutive parakeratosis

“…We could exclude that this degradation depends on DNase1, which is also expressed in differentiating keratinocytes 23 . Other candidate contributors to cornification-associated DNA fragmentation include, but are not limited to, caspase-activated DNase (CAD), also known as DNA fragmentation factor B 24 and the exonuclease TREX2 10, 25, 26 .…”

079 Inactivation of DNase1L2 and DNase2 in keratinocytes suppresses DNA degradation during epidermal cornification and results in constitutive parakeratosis

“…We could exclude that this degradation depends on DNase1, which is also expressed in differentiating keratinocytes 23 . Other candidate contributors to cornification-associated DNA fragmentation include, but are not limited to, caspase-activated DNase (CAD), also known as DNA fragmentation factor B 24 and the exonuclease TREX2 10,25,26 . Like in suppression of DNA breakdown during programmed cell death of hair and nail keratinocytes 14 and sebocytes 15 , the blockade of DNA degradation by deletion of DNase1L2 and DNase2 prevented the complete removal of histone H3, a component of nucleosomes, whereas the inter-nucleosomal histone H1 and a nuclear protein without DNA interaction, lamin A/C, were degraded.…”

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

“…The exonuclease TREX2 is the epidermis‐associated homolog of TREX1, which suppresses inflammation by controlling endogenous retroelements . Both TREX enzymes are expressed in the epidermis, but only TREX2 is upregulated during normal keratinocyte differentiation . Knockout of TREX2 is associated with the aberrant presence of DNA fragments in the cytoplasm of cornifying keratinocytes but not with inflammation .…”

“…Knockout of TREX2 is associated with the aberrant presence of DNA fragments in the cytoplasm of cornifying keratinocytes but not with inflammation . TREX2 and AIM2, a sensor of cytoplasmic DNA, are induced in psoriasis . DNase1L2 is another DNA‐degrading enzyme that is specifically expressed in cornifying keratinocytes where it cooperates both with TREX2 and DNase 2 .…”