MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice

Area of Science:

• Immunodermatology
• Molecular mechanisms of skin inflammation
• Genetic basis of psoriasis

Background:

• CARD14 gain-of-function mutations are linked to psoriasis pathogenesis.
• Mutant CARD14, BCL10, and MALT1 form a signaling complex, increasing NF-κB signaling and inflammation in keratinocytes.
• The cell-intrinsic role of CARD14 in psoriasis and the therapeutic potential of targeting MALT1 in vivo remain underexplored.

Purpose of the Study:

• To investigate whether psoriasis induced by CARD14 hyperactivation is keratinocyte-intrinsic.
• To evaluate the in vivo effect of MALT1 targeting on mutant CARD14-induced psoriasis.
• To explore MALT1 inhibition as a potential therapeutic strategy for psoriasis.

Main Methods:

• Generation of transgenic mice with inducible keratinocyte-specific expression of mutant CARD14 (CARD14^E138A).
• Keratinocyte-specific deletion of MALT1 in CARD14^E138A mice.
• Administration of a MALT1 protease inhibitor to CARD14^E138A mice.
• Assessment of skin phenotype, epidermal thickness, inflammation, and gene expression.

Main Results:

• Inducible keratinocyte-specific CARD14^E138A expression rapidly induced psoriatic skin features in mice, including epidermal thickening and inflammation.
• Increased expression of psoriasis-associated genes was observed in the skin of these mice.
• Both keratinocyte-specific MALT1 deletion and oral MALT1 inhibitor treatment significantly ameliorated psoriatic skin disease.
• These findings confirm a keratinocyte-intrinsic role for CARD14/MALT1 signaling in psoriasis development.

Conclusions:

• Enhanced CARD14/MALT1 signaling within keratinocytes plays a causal role in psoriasis pathogenesis.
• MALT1 protease activity is essential for the development of mutant CARD14-induced psoriatic skin disease.
• Targeting MALT1 protease represents a promising therapeutic approach for treating psoriasis.