Dry eye disease is the most common ocular surface disease globally, requiring a more effective treatment. We observed that a high-fat diet induced macrophage polarization to M1 and further induced inflammation in the meibomian and lacrimal glands. A four-week treatment with melatonin (MLT) eye drops can regulate macrophage polarization and alleviate dry eye signs. To investigate the therapeutic effects and mechanisms of action of MLT on high-fat-diet-induced dry eye disease in mice, RAW 264.7 cells pretreated with LPS and/or MLT underwent digital RNA with the perturbation of genes sequencing (DRUG-seq). Results showed that IFT27 was up-regulated, and MAPK pathways were suppressed after MLT pre-treatment. ERK/JNK phosphorylation was reduced in meibomian glands of MLT-treated dry eye mice and increased in IFT27 knockdown RAW 264.7 cells. In summary, MLT regulated macrophage polarization via IFT27 and reduced ERK/JNK phosphorylation. These results support that MLT is a promising medication for dry eye disease.

Pathogenesis and the associated risk factors of cataracts, glaucoma, and age-related macular degeneration (AMD) remain unclear. We aimed to investigate causal relationships between circulating cytokine levels and the development of these diseases. Genetic instrumental variables for circulating cytokines were derived from a genome-wide association study of 8293 European participants. Summary-level data for AMD, glaucoma, and senile cataract were obtained from the FinnGen database. The inverse variance weighted (IVW) was the main Mendelian randomization (MR) analysis method. The Cochran’s Q, MR-Egger regression, and MR pleiotropy residual sum and outlier test were used for sensitivity analysis. Based on the IVW method, MR analysis demonstrated five circulating cytokines suggestively associated with AMD (SCGF-β, 1.099 [95%CI, 1.037–1.166], P = 0.002; SCF, 1.155 [95%CI, 1.015–1.315], P = 0.029; MCP-1, 1.103 [95%CI, 1.012–1.202], P = 0.026; IL-10, 1.102 [95%CI, 1.012–1.200], P = 0.025; eotaxin, 1.086 [95%CI, 1.002–1.176], P = 0.044), five suggestively linked with glaucoma (MCP-1, 0.945 [95%CI, 0.894–0.999], P = 0.047; IL1ra, 0.886 [95%CI, 0.809–0.969], P = 0.008; IL-1β, 0.866 [95%CI, 0.762–0.983], P = 0.027; IL-9, 0.908 [95%CI, 0.841–0.980], P = 0.014; IL2ra, 1.065 [95%CI, 1.004–1.130], P = 0.035), and four suggestively associated with senile cataract (TRAIL, 1.043 [95%CI, 1.009–1.077], P = 0.011; IL-16, 1.032 [95%CI, 1.001–1.064], P = 0.046; IL1ra, 0.942 [95%CI, 0.887–0.999], P = 0.047; FGF-basic, 1.144 [95%CI, 1.052–1.244], P = 0.002). Furthermore, sensitivity analysis results supported the above associations. This study highlights the involvement of several circulating cytokines in the development ophthalmic diseases and holds potential as viable pharmacological targets for these diseases.