IL-33 alleviates corneal nerve damage in herpes simplex keratitis.

Herpes simplex keratitis (HSK) is a leading cause of corneal blindness globally, primarily resulting from herpes simplex virus type 1 (HSV-1) infection. HSK can cause pervasive and irreversible corneal nerve damage, leading to decreased corneal sensitivity and vision loss. Interleukin (IL)-33, a multifunctional cytokine, plays an important role in immune and inflammatory responses. However, the effects of IL-33 on nerve damage associated with HSK and the underlying mechanisms remain poorly understood. In this study, we first evaluated the effects of IL-33 on the severity of HSK and corneal nerve damage in a mouse model of HSK. The mechanisms of IL-33 on the production of neuroprotective factors by corneal epithelial cells (HCE-Ts) were investigated in an HSV-1 infection model in vitro. Additionally, the role and mechanism of IL-33 in regulating macrophage polarization for neuroprotection were investigated through in vitro co-culture experiments. The results indicated that IL-33 reduced the severity of HSK and protected corneal nerves in HSK mouse model. Mechanistically, IL-33 promoted the production of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) via activation of the GSK3β/β-catenin signaling pathway in corneal epithelial cells. Furthermore, IL-33 promoted M2 macrophage polarization through activation of the JAK2/STAT6 pathway, which in turn attenuated inflammatory responses and reduced neuronal apoptosis. These findings reveal the neuroprotective mechanisms of IL-33 in HSK and offer new insights for further research and treatment of HSK.