Role of Proinflammatory Cytokines in the Impaired Lacrimation Associated with Autoimmune Xerophthalmia

The primary function of the lacrimal gland is to secrete proteins, electrolytes, and water onto the ocular surface.1,2 The proteins secreted by the lacrimal gland have antibacterial and growth factor properties that are crucial for the homeostasis of the ocular surface.3 It is therefore not surprising that lacrimal gland fluid secretion is under tight neural control.4 Reflexes from the ocular surface and optic nerve, as well as from higher centers of the brain, stimulate lacrimal gland secretion by means of efferent parasympathetic and sympathetic nerves.4 Parasympathetic and sympathetic nerves innervate the acinar cells, duct cells, and blood vessels of the lacrimal gland. The parasympathetic nerves contain the neurotransmitters acetylcholine, which acts through cholinergic muscarinic receptors, and vasoactive intestinal peptide. Sympathetic nerves contain norepinephrine, which acts through adrenergic receptors.2 A decrease in lacrimal gland secretion is a primary cause of aqueous tear– deficient dry eye, and Sjogren syndrome is the leading cause of this type of dry eye.5,6 Sjogren syndrome is an autoimmune disease that occurs almost exclusively in women (>90%). The syndrome is associated with extensive lymphocytic infiltration of the lacrimal and salivary glands and destruction of epithelial cells. To date, there is no cure. The mechanisms responsible for the decreased tear and saliva secretion in Sjogren syndrome are still poorly understood. 6–9 It is believed that immune-mediated destruction of the epithelial cells, due to the progressive lymphocytic infiltration of the lacrimal and salivary glands, is responsible for the decline in tear and saliva production leading to dry eye and dry mouth.6–9 Recent studies have suggested that production of autoantibodies against acinar cell M3 muscarinic receptors may be also involved in the impaired production of tears and saliva.10,11 In previous studies in MRL/lpr mice, a murine model of human Sjogren syndrome, we have found that the lymphocytic infiltration of the lacrimal gland did not alter the parasympathetic, sympathetic, and sensory innervation of the remaining epithelial cells.12 We also found that acinar cells isolated from lacrimal glands of diseased MRL/lpr animals were responsive to exogenous cholinergic and adrenergic stimulation.13 Those findings suggest that neither a decrease in lacrimal gland innervation nor an alteration of the signaling pathways of the remaining epithelial cells could account for the decreased function of the lacrimal gland associated with Sjogren syndrome. In a recent report, we showed that activation with high KCl of nerves of MRL/lpr mouse lacrimal glands infiltrated with lymphocytes does not lead to the release of neurotransmitters that resulted in impaired protein secretion from this gland.14 Proinflammatory cytokine mediated inhibition of neurotransmitter release is now well documented. For example, several studies have shown that IL-1 β, IL-6, and TNFα inhibit acetylcholine and norepinephrine release from myenteric nerves.15–17 In a rat model of acute colitis, an inflammatory disease of the distal colon, IL-1β was implicated in blocking KCl-induced norepinephrine release from the myenteric plexus.18 In the hippocampus, IL-1β was shown to inhibit glutamate19 and norepinephrine release20 and to decrease the acetylcholine content.21 Based on these studies, we hypothesize that concomitant with inflammation of the lacrimal gland in MRL/lpr mice, there is an increase in the production of proinflammatory cytokines, especially IL-1β, that inhibits neurotransmitter release and leads to insufficient lacrimal gland secretion. The purpose of the present study was to test this hypothesis.