Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye

Area of Science:

• Ophthalmology
• Cell Biology
• Immunology

Background:

• Tear secretion maintains ocular surface hydration, involving both parasympathetic and sympathetic nervous systems.
• Intracellular calcium (Ca2+) elevation in lacrimal acinar cells is critical for tear secretion, but the Ca2+ channel in the sympathetic pathway remains under-investigated.

Purpose of the Study:

• To investigate the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in tear secretion.
• To analyze the Ca2+ channel responsible for Ca2+ elevation in the sympathetic pathway of tear secretion.

Main Methods:

• Examined tear secretion in mice lacking IP3R types 2 and 3 (Itpr2-/-;Itpr3-/- double-knockout mice).
• Measured intracellular Ca2+ elevation in lacrimal acinar cells following acetylcholine and epinephrine stimulation.
• Assessed ocular surface health, including keratoconjunctival alteration and corneal epithelial barrier integrity.
• Analyzed lacrimal glands for inflammatory cell infiltration and measured serum autoantibodies.

Main Results:

• Tear secretion was abolished in both parasympathetic and sympathetic pathways in Itpr2-/-;Itpr3-/- mice.
• Intracellular Ca2+ elevation was abolished in lacrimal acinar cells of these mice upon stimulation.
• Mice showed keratoconjunctival alterations and disrupted corneal epithelial barriers.
• Older Itpr2-/-;Itpr3-/- mice exhibited lacrimal gland inflammation and elevated serum autoantibodies, similar to Sjögren's syndrome markers.

Conclusions:

• IP3Rs are crucial for tear secretion in both major neural pathways.
• Itpr2-/-;Itpr3-/- mice represent a novel dry eye mouse model that recapitulates key features of Sjögren's syndrome.