Interleukin-17A regulates malignant T-cell proliferation via electron transport chain complex I

Abstract Cutaneous T-cell lymphoma (CTCL) is a rare malignancy of skin-resident T cells with clinically distinct subtypes characterized by an aberrant cytokine profile, notably elevated Interleukin-17A (IL-17A) levels. However, the functional importance of IL-17A dysregulation in the CTCL pathogenesis remains poorly understood. Immunofluorescence analysis of CTCL patient skin and flow cytometric analysis of blood samples ( n = 5) demonstrated increased IL-17A receptor (IL-17RA) levels in clinical biospecimens and T cell lymphoma cell lines. High-throughput label-free quantitative proteomic analysis of IL-17A-treated malignant T cells identified mitochondrial electron transport chain (ETC) complex I as a key protein enriched in IL-17A-induced cells. Further, we confirmed increased levels of ETC complex I via flow cytometry in IL-17A-stimulated T cell lymphoma cell lines and CTCL patients ( n = 9), highlighting the clinical relevance of the IL-17A-ETC complex I axis. Flow cytometric analysis also demonstrated increased levels of phosphorylated NF-κB-p65 (pS536). Functionally, IL-17A signaling was associated with increased ETC complex I activity and improved mitochondrial bioenergetics, including increased MMP and ATP levels. These metabolic changes correlated with increased malignant T-cell viability and survival. Genetic knockdown of IL-17RA reduced IL-17A-associated ETC complex I expression and abrogated cell survival. Consistently, pharmacological inhibition and genetic silencing of ETC complex I suppressed IL-17A-induced proliferation in vitro. Altogether, our data reveal the role of IL-17A signaling in the metabolic axis during T cell lymphoma progression and identify the IL-17A–ETC complex I axis as a potential therapeutic target providing mechanistic insights behind IL-17A-mediated metabolic rewiring.