Langerhans cells prevent subbasal nerve damage and upregulate neurotrophic factors in dry eye disease.

Eun Young Choi,Hyeon Chang Kim,Areum Yeo,Jong Suk Song,Chul Hee Lee,Myoung Joon Kim,Nayeong Gu,Hyun Goo Kang,Hyung Keun Lee,Hye Mi Noh

doi:10.1371/journal.pone.0176153

Eun Young Choi, Hyeon Chang Kim + Show 8 more

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https://doi.org/10.1371/journal.pone.0176153

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Abstract

The functional role of Langerhans cells (LCs) in ocular surface inflammation and nerve damage in dry eye (DE) disease has yet to be determined. This study was performed to investigate this relationship through both clinical study on DE patients and in vivo mouse models with induced DE disease. In a cross-sectional case-control study (54 eyes of DE patients; 34 eyes of control patients), average cell density, area, and process length of LCs were measured using confocal microscopy. Data were analyzed to determine whether changes in LCs are correlated with subbasal nerve plexus (SNP) parameters (nerve density, beading, and tortuosity). In DE patients, SNP density marginally decreased and nerve beading and tortuosity were significantly increased compared to the control group. The total number of LCs significantly increased in DE patients, and some LCs with elongated processes were found to be attached to nerve fibers. Interestingly, nerve loss and deformation were correlated with inactivation of LCs. In an in vivo experiment to elucidate the role of LCs in ocular surface inflammation and corneal nerve loss, we used a genetically modified mouse model (CD207-DTR) that reduced the population of CD207 (Langerin) expressing cells by injection of diphtheria toxin. In CD207-depleted mice with DE disease (CD207-dDTR+DE), corneal nerves in the central region were significantly decreased, an effect that was not observed in wild-type (WT)+DE mice. In CD207-dDTR+DE mice, infiltration of CD4+, CD19+, CD45+, and CD11b+ cells into the ocular surface was increased, as confirmed by flow cytometry. Increased IL-17 and IFN-γ mRNA levels, and decreased expression of neurotrophic factors and neurotransmitters, were also found in the CD207-dDTR+DE mice. These data support a functional role for LCs in negatively regulating ocular surface inflammation and exhibiting a neuroprotective function in DE disease.

Highlights

The precise pathophysiology of dry eye (DE) disease is unknown, immuno-inflammatory responses [1,2] and the loss of neural regulation between ocular surface and the lacrimal gland [3,4] are considered to be important contributing factors in DE initiation and progression
Aside from Langerhans cells (LCs) cell density, it is known that LC activation levels are an important factor in LC function and immuno-inflammatory status [36,37]
We found that the depletion of LCs was significantly correlated with the elevation of inflammatory levels in experimental DE status

Summary

Introduction

The precise pathophysiology of dry eye (DE) disease is unknown, immuno-inflammatory responses [1,2] and the loss of neural regulation between ocular surface and the lacrimal gland [3,4] are considered to be important contributing factors in DE initiation and progression. Langerhans cells (LCs), a subtype of dendritic cells (DCs), are the most potent antigen-presenting cells found in the epithelial layer. They are distinguishable from other DCs by their expression of Langerin or CD207 (a C-type lecitin) and Birbeck granules [14]. In vivo confocal microscopy (IVCM) has been used in several studies to describe the morphological and population changes of intraepithelial DCs (considered LCs in the DE disease affected cornea) [18,19], and an increased number of LCs with elongated processes have been found in both non-Sjogren’s syndrome and Sjogren’s syndrome patients [18]. There are few studies investigating the function of CD207+ cells (represented by LCs) in DE-induced pathogenesis

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