Investigating the Effect of IL-17 on Innervation

Abstract

The interleukin (IL)-17 family of cytokines is important in coordinating immunity and tissue homeostasis. While our lab recently identified that homeostatic IL-17 production coordinates whole-body metabolism, this cytokine is canonically defined by its pro-inflammatory contribution to the pathogenesis of diseases such as autoimmunity or cancer. Recently, these diverging roles have been unified in the context of nerve regulation: Disrupting IL-17 signaling can lead to reduced tissue innervation in both homeostatic and pathogenic settings. Because of its roles in driving pathogenesis and innervation, we hypothesize that IL-17 promotes sensory nerve growth and that this mechanism mediates tumor innervation. To test whether IL-17 directly induces nerve growth, we treated dorsal root ganglia (DRG) neurons with IL-17 or nerve growth factor (NGF)––a neurotrophic factor––and we quantified neuronal outgrowth and complexity. Next, we cultured DRG neurons with IL-17 and measured the expression of IL-17– or NGF-mediated genes associated with neuronal growth and downstream of IL-17 receptor or NGF receptor tropomyosin receptor kinase A. We determined that IL-17 promotes neurite outgrowth, and we elucidated structural and functional differences between IL-17A and IL-17F in regulating nerve growth. Given the emerging findings that IL-17 modulates innervation in tissues, we investigated if this regulation occurs in tumors by comparing tumor sizes and innervation patterns between IL-17 knockout and wild-type mice. Since tumor innervation is linked to increased metastasis and worse prognosis, our results suggest an unrecognized pro-tumor role of IL-17, which could lead to more aggressive cancer pathologies. Ultimately, this project reveals new insights into IL-17 biology, and these mechanisms may provide novel targets for cancer therapy.