Abstract
In psoriasis, keratinocytes are triggered by factors, such as infection or tissue damage, to release DNA, which thereby activates plasmacytoid dendritic cells and macrophages to induce inflammation, thickened epidermis, and parakeratosis. The recognition of double-stranded (ds)DNA facilitates the activation of cytoplasmic DNA sensors absent in melanoma 2 (AIM2) inflammasome assembly and cyclic guanosine monophosphate adenosine monophosphate (cGAMP) synthase (cGAS) - stimulator of interferon gene (STING) pathway, both of which play a pivotal role in mediating the inflammatory response and driving the progression of psoriasis. Additionally, secreted proinflammatory cytokines can stimulate further DNA release from keratinocytes. Notably, the activation of AIM2 and cGAS-STING signaling pathways also mediates programmed cell death, potentially enhancing DNA overproduction. As a result, excessive DNA can activate these pathways, amplifying persistent inflammatory responses that contribute to the maintenance of psoriasis. Several studies have validated that targeting DNA and its mediated activation of AIM2 and cGAS-STING offers promising therapeutic strategies for psoriasis. Here, we postulate a hypothesis that excessive cytosolic DNA can activate AIM2 and cGAS-STING, mediating inflammation and programmed cell death, ultimately fostering DNA accumulation and contributing to the development of psoriasis.