The DNA sensor AIM2 mediates psoriasiform inflammation by inducing type 3 immunity

Area of Science:

• Immunodermatology
• Molecular Biology
• Inflammation Research

Background:

• Psoriasis is a chronic inflammatory skin disease with unclear molecular drivers.
• The inflammation-related gene absent in melanoma 2 (AIM2) is linked to psoriasis susceptibility.
• Understanding AIM2's role is crucial for developing targeted psoriasis therapies.

Purpose of the Study:

• To investigate the role of absent in melanoma 2 (AIM2) in psoriasis pathophysiology.
• To elucidate the molecular mechanisms by which AIM2 contributes to psoriatic inflammation.

Main Methods:

• Analysis of AIM2 expression and mitochondrial DNA levels in human psoriatic epidermis and an imiquimod (IMQ)-induced mouse model.
• Genetic ablation of AIM2 and inflammasome components (ASC, caspase-1) to assess effects on IMQ-induced psoriasis.
• Investigation of IL-17A's effect on AIM2 expression in keratinocytes.

Main Results:

• Elevated mitochondrial DNA and high AIM2 expression were observed in psoriatic skin.
• Genetic absence of AIM2 reduced IMQ-induced psoriasis, decreasing type 3 cytokines (IL-17A, IL-23) and immune cell infiltration.
• IL-17A upregulated AIM2 expression in keratinocytes, and absence of downstream inflammasome components alleviated inflammation.

Conclusions:

• Absent in melanoma 2 (AIM2) plays a significant role in psoriasis development via canonical inflammasome activation.
• AIM2 contributes to psoriatic skin inflammation by promoting cytokine production and immune cell recruitment.
• Targeting the AIM2 inflammasome pathway presents a potential therapeutic strategy for psoriasis.