Psoriasis harbors multiple pathogenic type 17 T-cell subsets: Selective modulation by risankizumab.

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Single-cell studies reveal diverse Interleukin-17 (IL-17)-producing T cell (T17) subsets in human psoriasis.
• The differential regulation of these T17 subsets by IL-23 versus IL-17A blockade remains unclear.

Purpose of the Study:

• To investigate the distinct effects of systemic IL-23 versus IL-17A blockade on immune cell transcriptomes in psoriatic skin.
• To elucidate the specific T17 subset responses to IL-23 and IL-17A inhibition in the context of psoriasis.

Main Methods:

• Analysis of 93 human skin single-cell libraries from psoriasis patients (pretreatment and posttreatment) and healthy controls.
• Utilized single-cell RNA sequencing to compare transcriptomes after IL-23 or IL-17A inhibition.

Main Results:

• IL-23 inhibition downregulated pathogenic IL-17A+IFNG+ and IL-17F+IL10- T17 subsets expressing the IL-23 receptor.
• Nonpathogenic IL-17A+/IL-17F+ T17 cells, lacking IL-23 receptor, increased post-IL-23 inhibition.
• IL-23 inhibition led to greater induction of IL-17-negative regulation genes (e.g., TNFAIP3) in myeloid cells compared to IL-17A inhibition.

Conclusions:

• IL-23 inhibition modulates the psoriatic skin inflammatory environment through multiple immune mechanisms.
• Specific T17 subsets play critical roles in psoriasis pathogenesis and the maintenance of normal skin.
• Findings highlight differential therapeutic effects of targeting IL-23 versus IL-17A in psoriasis.