FUT1 deficiency elicits immune dysregulation and corneal opacity in steady state and under stress

Abstract

Fucosylation is a biological process that plays a critical role in multiple cellular functions from cell adhesion to immune regulation. Fucosyltransferases (FUTs) mediate fucosylation, and dysregulation of genes encoding FUTs is associated with various diseases. FUT1 and its fucosylated products are expressed in the ocular surface and ocular adnexa; however, the role of FUT1 in the ocular surface health and disease is yet unclear. Here, we investigated the effects of FUT1 on the ocular surface in steady-state conditions with age and under desiccating stress using a Fut1 knockout (KO) mouse model. We found that corneal epithelial defects and stromal opacity developed in Fut1 KO mice. Also, inflammatory responses in the ocular surface and Th1 cell activation in ocular draining lymph nodes (DLNs) were upregulated. Desiccating stress further aggravated Th1 cell-mediated immune responses in DLNs, lacrimal gland, and ocular surface in Fut1 KO mice, leading to severe corneal epithelial disruption and opacity. Mixed lymphocyte reaction assays revealed that the activity of splenocytes to stimulate CD4 T-cell proliferation was increased in Fut1 KO mice. Together, these data demonstrate that FUT1 deficiency induces immune dysregulation in the ocular surface and corneal opacity in steady state and under desiccating stress.

The Eyelid Meibomian Gland Deficiency in Fucosyltransferase 1 Knockout Mice

“…In the previous study, we observed higher numbers of corneal epithelial defects in Fut1 KO mice, both in a steady state and under desiccating stress, indicative of more severe DED, despite the fact that aqueous tear production from lacrimal glands or mucin-secreting goblet cells in the conjunctiva did not decrease defects in Fut1 KO mice [ 10 ]. This manifestation of severe DED in Fut1 KO mice might be due to the perturbation of MGs and their function associated with FUT1 deficiency, as we observed in the present study.…”

“…Fucosylation plays an important role in the regulation of inflammation and the immune response [ 10 , 14 ]. The eyelid inflammation often accompanies MGD in patients and has been reported to impair the structure and function of MGs [ 16 , 17 ].…”

“…It is well-known that fucosylation plays important indirect roles in immune responses by regulating cell adhesion, migration, differentiation, polarization and cell-to-cell interaction [ 14 ]. For example, we previously found that the Th1 immune response was upregulated in the ocular surface and the ocular draining lymph nodes in Fut1 KO mice [ 10 ]. It was also reported that fucosylation inhibition induced the upregulation of MHC class II and co-stimulatory molecules on dendritic cells [ 34 ].…”

“…Our group previously observed that FUT1 deficiency induced corneal epithelial defects and opacity at least in part by activating CD4 + T cells, but not by directly affecting lacrimal glands [ 10 ]. Rather, the aqueous tear production from lacrimal glands was increased in Fut1 knock-out (KO) mice, indicating reflex tearing in response to the ocular surface disruption.…”

Crosslinked Decellularized Porcine Pericardium as a Substrate for Conjunctival Reconstruction

“…Conjunctival goblet cells secrete mucins that are glycoproteins that play an important role in the ocular surface barrier function [ 43 ]. Numerous studies have revealed that ECM from decellularized tissues may provide a vital and functional microenvironment to support the growth and differentiation of goblet cells [ 44 ].…”