IL-33-Driven Macrophage Reprogramming as a Potential Immunometabolic Strategy for Herpes Simplex Keratitis

Area of Science:

• Immunology
• Virology
• Metabolism

Background:

• Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1), is a leading cause of infectious blindness.
• Macrophages are critical for antiviral immunity, but their metabolic regulation in HSK is not well understood.

Purpose of the Study:

• To investigate if interleukin-33 (IL-33) influences macrophage metabolism and function to improve antiviral protection against HSK.
• To identify the specific metabolic pathways involved in IL-33-mediated macrophage responses in HSK.

Main Methods:

• Bone marrow-derived macrophages (BMDMs) were stimulated with IL-33 and analyzed for phenotype and function.
• Integrated transcriptomic and metabolomic profiling identified key regulatory pathways.
• Adoptive transfer of IL-33-treated BMDMs into a mouse model of HSK was used for in vivo validation.

Main Results:

• IL-33 enhanced macrophage antiviral properties in vitro and in vivo, reducing viral load and disease severity in HSK models.
• A novel IL-33-lipoprotein lipase (LPL)-palmitoylcarnitine (L-PC) metabolic axis was identified.
• Inhibition of LPL abolished IL-33's protective effects, while L-PC supplementation partially restored them.

Conclusions:

• IL-33 reprograms macrophages into an antiviral phenotype via an LPL-dependent metabolic pathway, establishing an LPL-L-PC axis.
• Metabolic reprogramming of macrophages presents a potential strategy for preventing HSV-1-induced ocular disease.