Serine palmitoyltransferase (SPT) inhibition mitigates IL17A-mediated keratinocyte hyperproliferation through ROS-HIF1α axis.

Summary: Abstract Body: Interleukin 17A (IL17A) is pivotal in psoriasis pathogenesis and orchestrates keratinocyte hyperproliferation and the associated metabolic rewiring. Exploring IL17A-mediated lipid metabolic changes in keratinocytes is vital, as several lipids are known to drive this pathogenic proliferative phenotype. Specifically, IL17A increases sphingolipid levels in Human Keratinocytes (HKs) and also enhances the expression of a critical component of the committed step enzyme involved in the sphingolipid synthesis pathway, serine palmitoyltransferase long chain base subunit 2 (SPTLC2). Our study explores the functional relevance of IL17A-induced sphingolipid metabolic alterations in HKs by targeting the sphingolipid biosynthetic pathway. We performed western blotting and immunofluorescence imaging to validate IL17A-mediated upregulation in SPTLC2 levels in HKs. Additionally, immunofluorescence imaging of psoriasis biopsies showed elevated SPTLC2 levels compared to healthy controls (n=6, p<0.05), thus emphasizing its clinical relevance. Further, inhibition of SPT using myriocin not only reduces lipid levels in HKs, but interestingly also attenuates the formation of IL17A-driven cellular and mitochondrial reactive oxygen species (ROS) in HKs. Moreover, flow cytometric analysis showed that myriocin also lowers the IL17A-induced hypoxia-inducible factor 1α (HIF1α) levels in HKs, which is a crucial mediator in the IL17A-ROS-HIF1α axis. Accordingly, myriocin treatment also resulted in abrogation of IL17A-mediated hyperproliferation of HKs orchestrated by this axis. Overall, we uncover a previously unexplored connection between sphingolipid biosynthesis and IL17A-triggered redox imbalance through the ROS-HIF1α axis, which as a consequence, promotes keratinocyte hyperproliferation. Thus, inhibiting sphingolipid biosynthesis may offer a potential strategy for managing IL17A-driven psoriatic pathologies in keratinocytes. Vinanti V. Sawant¹, Soumitra Marathe¹, Ditipriya Mukherjee¹, Diksha Attrish¹, Bhavuk Dhamija¹, Moumita Basu¹, Abhijeet Sawant², Chitra Nayak², Rahul Purwar¹ 1. Indian Institute of Technology Bombay, Mumbai, India. 2. B.Y.L Nair Hospital, Mumbai, India. Cell Communication Networks and Stromal Biology