Extracutaneous manifestations of keratinocyte ferroptosis-driven chronic psoriatic inflammation.

Summary: Abstract Body: It is well-known that keratinocytes (KCs) play a critical role in the initial and chronic phases of psoriasis. However, the mechanism of KC-immune crosstalk which initiates and maintains skin and systemic inflammatory loops in psoriasis has not been established. Recently, we discovered that a prominent feature of psoriasis is an accumulation of pro-ferroptotic oxidized polyunsaturated fatty acid (PUFA)-phosphatidylethanolamine (PE) species (oxPE) in KCs, associated with upregulation of arachidonate 15-lipoxygenase type II (Alox15B or 15-Lox-2, which generates oxPE species) and downregulation of glutathione peroxidase 4 (Gpx4, which reduces oxPE). Strikingly, genetic ablation of Gpx4 in only a small fraction of keratin 14+ KCs in mouse epidermis (K14/Gpx4 model) produced psoriasis-like skin phenotype and systemic inflammation, including arthritis, closely resembling human disease with characteristic activation of canonical signaling pathways and multi-omics biomarkers. Furthermore, depletion of T lymphocytes, current standard-of-care biological anti-IL-12/IL-23/TNFα therapies, and, most importantly, inhibitors of 15-Lox-2 and oxidized phospholipids (oxPLs) were able to reverse psoriasiform disease in mice. We also found that aged K14/Gpx4 mice develop signs characteristic to psoriatic arthritis in forepaws and hindpaws, including dactylisis, loss of retraction reflexes, significant weakening of grip strength, and demonstrated increased arthritis score. In addition, CT radiography of paws revealed marked bone erosion and proliferation with distal predominance, ‘pencil in cup’ deformities, ankylosis and phalangeal osteolysis, while histology showed synovial proliferation and bone destruction, dactylitis, and enthesitis. Such arthritis-like extracutaneous inflammation, which occurs after the initial immune responses to KC ferroptosis in the skin, suggests an autoreactive T cell-mediated process which expands from skin to other organs. Kunal Singh¹, Kavita Vats¹, Yuri Bunimovich^{1, 2, 3} 1. Dermatology, University of Pittsburgh, Pittsburgh, PA, United States. 2. Immunology, University of Pittsburgh, Pittsburgh, PA, United States. 3. UPMC Hillman Cancer Center, Pittsburgh, PA, United States. Cell Communication Networks and Stromal Biology