Immunomodulatory Role of Neuropeptides in the Cornea

Abstract

The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.

Topical application of calcitonin gene-related peptide as a regenerative, antifibrotic, and immunomodulatory therapy for corneal injury

“…We cultured human CEnC and found that the inflammatory cytokine TNF- 10,61 results in apoptosis and activation of apoptotic genes Cas3 and Bax in vitro. CEnC express CGRP receptors CLR, RAMP2 62 and we found that CGRP treatment protects them from TNF--mediated apoptosis and cell loss. This cyto-protective function of CGRP in CEnC is consistent with reports in cardiac fibroblasts and vascular endothelial cells 63,64 .…”

“…It has an array of physiological functions through binding to calcitonin receptor-like (CLR) and receptor activity-modifying (RAMPs) receptors [20][21][22] . While corneal nerves express high levels of CGRP, its receptors have been found in the corneal epithelium, stroma, and endothelium 17 . Upon binding to CLR-RAMP1, CGRP activates adenylyl cyclase, increases intracellular cAMP concentration, and subsequently activates protein kinase A, C and MAP kinase which regulates epithelial migration and proliferation 23 .…”

Cord blood-derived biologics lead to robust axonal regeneration in benzalkonium chloride-injured mouse corneas by modulating the Il-17 pathway and neuropeptide Y

“…This observation was consistent with previous studies, which demonstrated the role of inflammation in promoting axonal regeneration (Mietto et al 2015 ; Bollaerts et al 2017 ; Leon et al 2000 ; Hauk et al 2010 ). Additional evidence of how inflammation might be related to axon regeneration was revealed in the prominent downregulation of Npy , a neuropeptide expressed by corneal sympathetic nerves (Puri et al 2022 ), in the saline group, which corresponded to heightened gene expression of its known downstream targets ( Il6 , Nfkb1, Il1b, Cd80 , and Cd86 ) (Chen et al 2020 ; Ferreira et al 2011 ; Ding et al 2021 ). This trend was reversed when UCS and UCPRP were administered, indicating that these treatments were able to elevate the expression of Npy following BAK injury and subsequently reduce the expression of the immune-related genes.…”

Roles of biomaterials in modulating the innate immune response in ocular therapy

“…These DCs can produce antiinflammatory cytokines such as IL-10, TGF-β, and indoleamine 2, 3-dioxygenase (IDO) to suppress T-cell activity and function in maintaining ocular tolerance. Tolerogenic DCs can be generated in vitro with the co-culture of stromal cells or by treatment with immunosuppressive agents such as IL-10, TGF-β, vitamin D receptor agonists, and vasoactive intestinal peptide (VIP) (Dempsey et al, 2003;Hu and Wan, 2011;Haneklaus et al, 2012;Perez and Caspi, 2015;Puri et al, 2022). Although tolerogenic DCs demonstrated therapeutic strengths in autoimmune diseases, the exploration of their potential in the ocular field is still under investigation.…”