Inhibiting myeloid-lineage mTOR alleviates psoriasis-like reponse in vivo in imiquimod-induced dermatitis in mice

Summary: Abstract Body: While therapeutic advancements have improved disease management, psoriasis’ pathogenesis remain underexplored. We recently demonstrated that inhibition of mTOR signaling by phytochemicals, like fisetin mitigate inflammation and psoriasis development in a 3D human skin model of psoriasis. But the significance of mTOR signaling inhibition in inflammation-related cells, particularly myeloid-lineage cells, and their contribution to psoriasis development, remains poorly understood. In this study, we investigated the impact of deleting mTOR signaling in myeloid cells using a novel genetic model of myeloid-specific mTOR knockout (mTORmyeKO) mice subjected to an imiquimod (IMQ)-induced psoriasis-like model. mTORmyeKO mice demonstrated significantly reduced psoriasiform skin lesions, marked by lower Psoriasis Area and Severity Index (PASI) scores, decreased epidermal thickness, and attenuation of hyperplasia and parakeratosis compared to wild-type controls (p<0.05). Histological and immunostaining analyses revealed reduced activation and infiltration of CD11c+ dendritic cells and CD3+ T cells, along with diminished keratin 14 expression, a hallmark of hyperproliferative keratinocytes. Dermal inflammatory infiltrates, including helper T cells and macrophages, were markedly suppressed in mTORmyeKO mice (p<0.05), underscoring the pivotal role of myeloid-derived mTOR signaling in psoriasis pathogenesis. Mechanistic insights identified a significant reduction in pro-inflammatory lipid kinases, such as PIP5K1 (p<0.05), linking mTOR activity to lipid signaling pathways critical for keratinocyte and immune cell crosstalk. These findings establish myeloid-specific mTOR signaling as a central regulator of the inflammatory and proliferative cascades underpinning psoriasis. Our findings highlight a novel therapeutic avenue by targeting myeloid-derived mTOR signaling, providing a foundation for precision therapies to mitigate systemic inflammation and hyperproliferation in psoriasis and related inflammatory disorders. JC Chamcheu¹, Tithi Roy¹, Tolulope O. Omolekan¹ 1. Pathobiological Sci Department, Louisiana State University, Baton Rouge, LA, United States. Translational Studies: Preclinical