Psoriasis, a metabolic dysregulation of the innate immune system?

Grantee: Antonio Postigo, Professor, IDIBAPS, Barcelona, Spain

Amount: DKK 3,672,274

Targeting ZEB1 in macrophages as a new therapeutic approach to psoriasis.

Psoriasis involves deregulation of the innate and adaptive immunities. The metabolism of T cells as well as of keratinocytes is altered in psoriasis. Metabolism also controls the immunogenic versus tolerogenic responses of macrophages through mechanisms still not fully understood.

Our preliminary data indicate that: 1) the transcription factor ZEB1 is downregulated in the skin of psoriatic patients and of mouse models of psoriasis as well as in the peripheral blood monocytes/macrophages of psoriatic patients; 2) ZEB1 expression in macrophages ameliorates psoriatic lesions in mice; 3) Mechanistically, ZEB1 regulates macrophage tolerogenic responses in psoriasis by inhibiting mitochondrial activity and reducing pro-inflammatory cytokines and ROS.

The project will investigate: 1) the molecular mechanisms by which ZEB1 modulates macrophage response in psoriasis; 2) the expression, role, and mechanism of action in psoriasis of the related factor ZEB2, which has opposing roles to ZEB1 in other contexts; 3) ZEB factors in macrophages as therapeutic targets in psoriasis.

Implementing this project will be impactful as it will explore a new pathogenic mechanism and inform the design of safer and more targeted therapies to improve the quality of life of psoriatic patients. The proposal is innovative both conceptually—proposing unexpected immunoregulatory roles for ZEB1/2—and methodologically—using unique mouse models and bridging macrophage biology, gene regulation, and metabolism.