Proteomic profiling reveals immunomodulatory role of IL-33 in ocular bacterial and fungal infections

Bacterial and fungal pathogens are major causes of infectious endophthalmitis following eye surgery or trauma, often leading to vision impairment or blindness. The distinct clinical outcomes observed in bacterial and fungal endophthalmitis suggest differences in host immune responses. To investigate these differences, we utilized cytokine arrays and murine models of bacterial (<i>Staphylococcus aureus</i>) and fungal (<i>Aspergillus fumigatus</i>) endophthalmitis. Our analysis revealed that cytokine responses peaked in bacterial infections at 12-24 h, whereas fungal infections exhibited a delayed peak at 48 h. Several inflammatory mediators, including MMP9, MMP3, CD14, LIX, LCN2, retinol-binding protein 4, ICAM1, and VCAM1, were differentially elevated. Notably, interleukin-33 (IL-33) levels peaked early in bacterial infections but continued to rise throughout all time points in fungal endophthalmitis. Analysis of patient vitreous samples further confirmed higher levels of IL-33 in bacterial (<i>n</i>=40) and fungal (<i>n</i>=20) endophthalmitis cases. Functional studies in IL-33-deficient mice revealed an increased fungal burden and elevated TNF-α and IL-6 levels, but bacterial endophthalmitis severity remains largely unaffected. Additionally, bone marrow-derived macrophages from IL-33^-/- mice exhibited increased cell death in response to fungal and bacterial infection. Our findings reveal divergent innate immune responses between bacterial and fungal endophthalmitis and emphasize the immunomodulatory function of IL-33 in ocular infections.