FAM3C/ILEI protein is elevated in psoriatic lesions and triggers psoriasiform hyperproliferation in mice

• Published in: EMBO molecular medicine Vol. 15; no. 7; pp. e16758 - n/a
• Main Authors: Malik, Barizah, Vokic, Iva, Mohr, Thomas, Poppelaars, Marle, Holcmann, Martin, Novoszel, Philipp, Timelthaler, Gerald, Lendl, Thomas, Krauss, Dana, Elling, Ulrich, Mildner, Michael, Penninger, Josef M, Petzelbauer, Peter, Sibilia, Maria, Csiszar, Agnes
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.07.2023; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: AKT protein; Animals; Biomedicine; Breast cancer; Chemokines; Cytokines; Cytokines - metabolism; EMBO38; Genotype & phenotype; ILEI/FAM3C; Inflammation; keratinocyte differentiation; Keratinocytes; Leukocytes (neutrophilic); Metastases; Metastasis; Mice; Molecular Medicine; Phosphorylation; Proteins; Psoriasis; Signal Transduction; Skin diseases; Stat3 protein; Therapeutic targets; Transcriptomics; U-Plasminogen activator; uPA/PLAU; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; keratinocyte differentiation; uPA/PLAU; inflammation; ILEI/FAM3C; psoriasis
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202216758

FAM3C/ILEI is an important cytokine for tumor progression and metastasis. However, its involvement in inflammation remains elusive. Here, we show that ILEI protein is highly expressed in psoriatic lesions. Inducible keratinocyte‐specific ILEI overexpression in mice ( K5‐ILEI ind ) recapitulates many aspects of psoriasis following TPA challenge, primarily manifested by impaired epidermal differentiation and increased neutrophil recruitment. Mechanistically, ILEI triggers Erk and Akt signaling, which then activates STAT3 via Ser727 phosphorylation. Keratinocyte‐specific ILEI deletion ameliorates TPA‐induced skin inflammation. A transcriptomic ILEI signature obtained from the K5 ‐ ILEI ind model shows enrichment in several signaling pathways also found in psoriasis and identifies urokinase as a targetable enzyme to counteract ILEI activity. Pharmacological inhibition of urokinase in TPA‐induced K5‐ILEI ind mice results in significant improvement of psoriasiform symptoms by reducing ILEI secretion. The ILEI signature distinguishes psoriasis from healthy skin with uPA ranking among the top “separator” genes. Our study identifies ILEI as a key driver in psoriasis, indicates the relevance of ILEI‐regulated genes for disease manifestation, and shows the clinical impact of ILEI and urokinase as novel potential therapeutic targets in psoriasis. Synopsis Analyses of human psoriatic skin and studies in genetically engineered mouse models revealed that FAM3C/ILEI contributes to psoriasis by controlling keratinocyte hyperproliferation, differentiation and neutrophil recruitment and identifies uPA, a regulator of ILEI secretion, as a druggable target. ILEI protein expression and regulators of its translation and activation were upregulated in psoriatic skin lesions. Mice with keratinocyte‐specific ILEI overexpression ( K5‐ILEI ind ) developed psoriasis‐like skin symptoms following TPA challenge. Keratinocyte‐specific ILEI overexpression contributed to impaired differentiation, increased hyperproliferation, and transcriptional upregulation of neutrophil‐recruiting factors in a cell‐intrinsic manner. Upon inflammation, keratinocyte‐specific ILEI expression generated a feed‐forward loop on the own secretion by the autocrine upregulation of uPA transcription. uPA was validated as therapeutic target in K5‐ILEI ind transgenic mice and proposed as being part of a “psoriasis ILEI gene signature” with strong relevance in human disease manifestation. Graphical Abstract Analyses of human psoriatic skin and studies in genetically engineered mouse models revealed that FAM3C/ILEI contributes to psoriasis by controlling keratinocyte hyperproliferation, differentiation, and neutrophil recruitment and identifies uPA, a regulator of ILEI secretion, as a druggable target.