Dry eye is the most common ocular surface disease with increasing prevalence worldwide. Dry eye disease is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological role [1,2]. This advanced definition not only updated our understanding of dry eye disease but also provided new direction for therapeutic research.

Based on the new concept, tear hyperosmolarity has been recognized as one of the core mechanisms in dry eye diseases. Patients with dry eye disease may suffer from reduced production and/or increased evaporation of aqueous tear phase, which results in tear hypertonicity [3]. Tear film instability and hyperosmolarity may cause ocular surface irritation symptoms, inflammation and corneal barrier disruption, which further lead to cells damage and apoptosis, as well as goblet cell loss [4].

Osmoprotective topical treatment was designed specifically to address hyperosmolarity in dry eye disease [5]. Osmoprotectants, as small molecules and compatible solutes, do not perturb cellular macromolecules, and can restore isotonic cell volume and stabilize protein function, allowing adaptation to hyperosmolarity [6,7]. Compatible solutes act as osmoprotectants in a variety of ways. For example, trehalose, a stabilizing compatible solute, can promote protein stabilization under heating, freezing, and desiccation situation [6]. Other compatible solutes may have some cytoprotective effects, such as antioxidation, redox balancing in hypoxic conditions, sulphide detoxification, and Ca2+ modulation [[8], [9], [10]].

Ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) is such a compatible water molecule-binding solute and naturally produced by special bacterial species, which survive well in the unfavorable extreme environment [11,12]. Serving as Osmoprotectant, ectoine can protect cells against radiation or osmotic stress, meanwhile, it can accumulate inside cells at high concentrations without interfering with the natural processes [11]. The mechanism of ectoine is called “preferential hydration”: Ectoine does not directly bind to proteins or cells membrane; indeed, it works by excluding osmolytes from the proteins and membranes, which will stabilize their native confirmation and making them less vulnerable to external stress [13]. In addition to its preferential exclusion effect, it can also limit the inflammatory cascade in respiratory and skin cells [14].

Ectoine is widely used in many diseases where membrane protection is fundamental. For examples, topical application of ectoine has been used to skin lesions for relieving the symptoms of atopic dermatitis [15], and used to treat Rhinitis Sicca anterior and acute pharyngitis [16]. For ocular disease, ectoine eye drops have been recently used outside the USA to treat seasonal allergic rhinoconjunctivitis [17,18].

However, the protective role and molecular mechanism of ectoine in dry eye disease are largely unknown. In the present study, we explored the potential role of ectoine in protecting corneal epithelial cell survival and barrier function by promoting an anti-inflammatory cytokine IL-37, which suppressed the proinflammatory cytokines and cathepsin S induced by hyperosmotic stress, an in vitro dry eye model using primary human corneal epithelial cells (HCECs).