Dry Eye Disease and Tear Cytokine Levels—A Meta-Analysis

Roda, Matilde; Corazza, Ivan; Reggiani, Maria Letizia Bacchi; Pellegrini, Marco; Taroni, Leonardo; Giannaccare, Giuseppe; Versura, Piera

doi:10.3390/ijms21093111

Cited by 100 publications

(60 citation statements)

References 30 publications

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“…Abnormal increased inflammatory factors, including 1β, IL-6, IL-8, IL-10, interferon-γ, IFN-γ, and tumor necrosis factor-α, however, evidence was less strong for IL-2 and IL-17A. 25 While it was found that Th17 was a key immune cell that demonstrated main role in chronic ocular surface disorders. 26 The IL-17 cytokine family was named CTLA8 when it was discovered in 1993.…”

Section: Discussionmentioning

confidence: 98%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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Background Hyperosmosis stress (HS) was a key pathological factor in the development of dry eye disease (DED). Nicotinamide mononucleotide (NMN) demonstrated protective effects in the corneal damage, however, its role in the HS-induced DED remained unclear. Methods A NaCl based HS in-vitro model (500 mOsm) was generated and used in a co-culture system including corneal epithelial cells (CEC) and macrophage cell line RAW264.7. The effect of NMN on NAD+ metabolism and the expression of HS biomarker, tonicity-responsive element binding protein (TonEBP), was studied in the CEC. The cellular activity, including cell viability, apoptosis status and lactate dehydrogenase (LDH) release through trypan blue staining, flow cytometry and LDH assay, respectively. The mitochondrial membrane potential (MMP) assay would be conducted using the JC1 kit. The expression of IL-17a were detected using RT-PCR, ELISA and Western blot. After co-culture with the CEC in different group for 24 h, the phagocytosis ability and macrophage polarization were assessed in RAW264.7 cells co-cultured with CEC with or without HS or NMN treatment. Besides, the involvement of Notch pathway in the RAW264.7 would be analyzed. The potential involvement of Sirtuin 1 (SIRT1) and IL-17a in the crosstalk between CEC and macrophage was studied with SIRT1 inhibitor EX 527 and anti-IL-17a monoclonal antibody, respectively. Results NMN treatment increased NAD+ concentration and thus improved cell viability, reduced apoptotic rate and decreased the LDH release in HS-treated CEC. Besides, NMN alleviated HS-induced MMP, intracellular ROS and LDH release. Besides, it was confirmed NMN improve SIRT1 function and decreased the HS related IL-17a expression in CEC and then alleviated macrophage phagocytosis ability and M1 polarization based on a CEC-macrophage co-culture system. Moreover, NMN treatment of CEC in the CEC could moderate the subsequent macrophage activation through Notch pathway. SIRT1 activation and IL-17a inhibition was regarded as key progress in the function of NMN based on the application of EX 527 and anti-IL-17a antibody in the CEC-macrophage co-culture system. Conclusion The findings demonstrated that NMN could alleviated HS-induced DED status through regulating the CEC/macrophage interaction. Our data pointed to the role of SIRT1, IL-17a and Notch pathway in the function of NMN and then provided updated knowledge of potential NMN application in the management of DED.

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Section: Discussionmentioning

confidence: 98%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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“…Furthermore, previous studies have reported a significant correlation between low levels of tear lactoferrin and the development of both dry eye disease (DED) and chronic meibomitis [ 18 , 19 , 20 ] ( Figure 2 A). These two common disorders of the ocular surface system share a degree of mutual pathophysiology, since markers of inflammation and oxidative stress are present in both conditions [ 21 ]. Indeed, a decreased volume and an altered qualitative composition of tear film, together with excessive tear evaporation, lead to the creation of a hyperosmolar environment, which then initiates both inflammatory and oxidative cascades, resulting in impaired epithelial proliferation and differentiation [ 22 ].…”

Section: Lactoferrin and Dry Eyementioning

confidence: 99%

Therapeutic Effects of Lactoferrin in Ocular Diseases: From Dry Eye Disease to Infections

Vagge

Senni

Bernabei

et al. 2020

IJMS

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Lactoferrin is a naturally occurring iron-binding glycoprotein, produced and secreted by mucosal epithelial cells and neutrophils in various mammalian species, including humans. It is typically found in fluids like saliva, milk and tears, where it reaches the maximum concentration. Thanks to its unique anti-inflammatory, antioxidant and antimicrobial activities, topical application of lactoferrin plays a crucial role in the maintenance of a healthy ocular surface system. The present review aims to provide a comprehensive evaluation of the clinical applications of lactoferrin in ocular diseases. Besides the well-known antibacterial effect, novel interest has been rising towards its potential application in the field of dry eye and viral infections. A growing body of evidence supports the antimicrobial efficacy of lactoferrin, which is not limited to its iron-chelating properties but also depends on its capability to directly interact with pathogen particles while playing immunomodulatory effects. Nowadays, lactoferrin antiviral activity is of special interest, since lactoferrin-based eye drops could be adopted to treat/prevent the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, which has conjunctivitis among its possible clinical manifestations. In the future, further data from randomized controlled studies are desirable to confirm the efficacy of lactoferrin in the wide range of ocular conditions where it can be used.

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“…Indeed, zileuton produced additional, more specific anti-inflammatory effects. The first specific effect was the pronounced upregulation of IL-10, the anti-inflammatory cytokine previously found to be associated with DES [68]. Interestingly, a similar effect of zileuton against IL-10 was demonstrated in other inflammation-related disorders [69].…”

Section: Discussionmentioning

confidence: 66%

Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms

et al. 2020

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Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways).

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Dry Eye Disease and Tear Cytokine Levels—A Meta-Analysis

Cited by 100 publications

References 30 publications

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Therapeutic Effects of Lactoferrin in Ocular Diseases: From Dry Eye Disease to Infections

Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms

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