Original articleInflammation in Dry Eye Disease: How Do We Break the Cycle?
Section snippets
Establishment of Inflammation's Critical Role in Dry Eye Disease
Dry eye disease (DED) is a heterogeneous disorder of the ocular surface in which the common denominator is inflammation. The recognition of inflammation as a critical driver is reflected by its inclusion in the Dry Eye Workshop1 definition of DED: “Dry eye disease is a multifactorial disorder of the tears and ocular surface, associated with symptoms of discomfort, visual disturbance, and tear film instability. It is accompanied by increased osmolarity of the tear film and inflammation of the
Neuronal Feedback Loop
The lacrimal functional unit, defined as the ocular surface, lacrimal gland, and their neural interconnectivity, maintains ocular surface homeostasis, and disruption of this leads to tear film instability.1, 5 Tear production is regulated through a neural reflex loop; stimulation of nerves at the ocular surface or nasal mucosa sends impulses to the brain via the fifth cranial nerve, triggering a reflex response via nerves passing to the lacrimal glands. Pain, microbial or environmental insult,
Players in the “Vicious Circle” of Inflammation
The inflammatory cycle consists of afferent and efferent arms (Figs 1 and 2).1, 9, 10, 25 The afferent arm consists of stress to the ocular surface (environmental, endogenous, microbial, or a combination thereof, as well as hormone imbalance and genetic factors). When there is excess stress, production of cytokines, matrix metalloproteinases (MMPs), and chemokines ensues. This inflammatory setting prompts the maturation of antigen-presenting cells (APCs) and resident dendritic cells in the
How Do We Break the Inflammatory Cycle?
To date, 2 commercially available topical medications have emerged based on the recognition of inflammation as the fundamental driver of DED. Topical cyclosporine 0.05% was approved by the United States Food and Drug Administration in 2002. Cyclosporine acts as a T-cell inhibitor and also decreases expression of HLA-DR (a major histocompatibility complex class II cell surface receptor involved in antigen presentation) and IL-6.31, 32 Several studies consistently have shown improvement in signs
Conclusions
Dry eye disease is a heterogeneous disorder of the ocular surface in which the common denominator is inflammation; it is both a cause and effect of the disease. Currently, 2 Food and Drug Administration–approved medications (topical cyclosporine 0.05% and topical lifitegrast 5%) are directed at the inflammatory component of DED. Many therapeutic targets in the inflammatory cascade have been identified, as evidenced by the numerous mechanisms of action of various medications being studied.
References (61)
- et al.
Epstein-Barr virus infection and immunologic dysfunction in patients with aqueous tear deficiency
Ophthalmology
(1990) The pathology of dry eye
Surv Ophthalmol
(2001)A new approach for better comprehension of diseases of the ocular surface
J Fr Ophthalmol
(2007)- et al.
Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting
Ocul Surf
(2013) - et al.
Autoimmunity at the ocular surface: pathogenesis and regulation
Mucosal Immunol
(2010) - et al.
Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye
Exp Eye Res
(2006) - et al.
IL-17 disrupts corneal barrier following desiccating stress
Mucosal Immunol
(2009) - et al.
A novel pro-lymphangiogenic function for Th17/IL-17
Blood
(2011) - et al.
Lifitegrast, a novel integrin antagonist for treatment of dry eye disease
Ocul Surf
(2016) - et al.
Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1)
Cell
(1987)
Cytokine modulation of human corneal epithelial cell ICAM-1 (CD54) expression
Exp Eye Res
Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study
Ophthalmology
Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study
Ophthalmology
Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3)
Ophthalmology
Treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop: prospective double-blind randomized study
Cont Lens Anter Eye
Doxycycline inhibition of interleukin-1 in the corneal epithelium
Am J Ophthalmol
Dietary polyunsaturated fatty acids and inflammatory mediator production
Am J Clin Nutr
Sjogrens syndrome as failed local immunohomeostasis: prospects for cell-based therapy
Ocul Surf
Impact of gender on exocrine gland inflammation in mouse models of Sjogren's syndrome
Exp Eye Res
The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop
Ocul Surf
Histology of the lacrimal gland in keratoconjunctivitis sicca
Br J Ophthalmol
Senile atrophy of the human lacrimal gland: the contribution of chronic inflammatory disease
Br J Ophthalmol
The pathology of dry eye: the interaction between the ocular surface and lacrimal glands
Cornea
Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eye
Invest Ophthalmol Vis Sci
Desiccating stress induces T cell-mediated Sjögren's syndrome-like lacrimal keratoconjunctivitis
J Immunol
Dry eye as a mucosal autoimmune disease
Int Rev Immunol
Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells
Invest Ophthalmol Vis Sci
Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface
Eye Contact Lens
Dry eye disease: an immune-mediated ocular surface disorder
Arch Ophthalmol
Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-γ
Invest Ophthalmol Vis Sci
Cited by (85)
Sialylated IVIg promotes clinical improvements in a rabbit dry eye model by regulating inflammatory cytokines
2024, Experimental Eye ResearchLayer-by-layer oral-deliverable nanoparticles targeted microfold cells to promote lutein absorption in alleviating dry eye disease
2024, Chemical Engineering JournalIn situ formation of injectable organogels for punctal occlusion and sustained release of therapeutics: design, preparation, in vitro and in vivo evaluation
2023, International Journal of PharmaceuticsPolymer- and lipid-based nanocarriers for ocular drug delivery: Current status and future perspectives
2023, Advanced Drug Delivery ReviewsSimultaneous determination of Panax notoginseng total saponins in rabbit tears by UPLC-QqQ-MS/MS and its application to pharmacokinetic study
2023, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Statement of Potential Conflict of Interest and Funding/Support: See page S19.
Financial Disclosure(s): The author(s) have made the following disclosure(s): M.K.R.: Consultant – The Eye-Bank for Sight Restoration; Financial support – The Eye-Bank for Sight Restoration, Pentavision, Ophthalmology Management, Eurobio; Expert testimony – The Expert Institute; Equity owner – AMO, Gilead, Ophthotech
F.S.M.: Consultant and speakers’ bureaus – Allergan and Shire.
Author Contributions:
Conception and design: Mah, Rhee
Analysis and interpretation: Mah, Rhee
Data collection: Mah, Rhee
Obtained funding: none
Overall responsibility: Mah, Rhee