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Review
. 2022 Aug 16;10(8):1985.
doi: 10.3390/biomedicines10081985.

Immunomodulatory Role of Neuropeptides in the Cornea

Sudan Puri  1   2 , Brendan M Kenyon  1   3 , Pedram Hamrah  1   2   3   4   5
Affiliations
Review

Immunomodulatory Role of Neuropeptides in the Cornea

Sudan Puri et al. Biomedicines. .

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.

Keywords: antigen-presenting cells; cornea; immune cells; kinetics; neuroimmune interactions; neuropeptides; ocular immune privilege; ocular surface; receptors; trafficking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Neuropeptides interact with their G protein-coupled receptors (GPCRs) and the β/γ dimer is separated from the Gα subunit classified as Gs, Gq/11, or Gi/o, which transduce the signal intracellularly via effector proteins. Adapted from “GPCR Effector Pathways”, by BioRender.com accessed on 26 July 2022. Retrieved from https://app.biorender.com/biorender-templates accessed on 12 April 2022. SP—Substance P, CGRP—calcitonin gene-related peptide, AM—adrenomedullin, VIP—vasoactive intestinal peptide, PACAP—pituitary Adenylyl Cyclase activating peptide, NPY—neuropeptide Y, SST—somatostatin.
Figure 2
Figure 2
Neuropeptide Substance P and neurokinin receptor: (a) transcription and synthesis of SP (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of Substance P (https://pubchem.ncbi.nlm.nih.gov/compound/36511#section=2D-Structure, accessed on 22 October 2021); (c) bound-state structure representation of Substance P (brown) to NK1R (green). The solution conformation of Substance P in water was complexed with NK1R. Image from the RCSB PDB (rcsb.org) of PDB ID 2KS9 [73].
Figure 3
Figure 3
Neuropeptide CGRP and CLR receptor: (a) transcription and synthesis of CGRP (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of CGRP (https://pubchem.ncbi.nlm.nih.gov/compound/16132372#section=2D-Structure, accessed on 22 October 2021); (c) Crystal structure of a CGRP receptor ectodomain heterodimer with bound high-affinity inhibitor. Image from the RCSB PDB (rcsb.org) of PDB ID 6ZHO [309].
Figure 4
Figure 4
Neuropeptide AM and receptors: (a) transcription and synthesis of AM (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of AM (https://pubchem.ncbi.nlm.nih.gov/compound/56841671#section=2D-Structure, accessed on 22 October 2021); (c) CryoEM structure of the active adrenomedullin 1 receptor G protein complex with adrenomedullin peptide. Image from the RCSB PDB (rcsb.org) of PDB ID 6UUN [85].
Figure 5
Figure 5
Neuropeptide VIP: (a) transcription and synthesis of VIP (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of VIP (https://pubchem.ncbi.nlm.nih.gov/compound/53314964#section=2D-Structure, accessed on 22 October 2021); (c) crystal structure of B*27:06 bound to the pVIPR peptide. Image from the RCSB PDB (rcsb.org) of PDB ID 5DEG [368].
Figure 6
Figure 6
Neuropeptide PACAP and PAC1R: (a) transcription and synthesis of PACAP (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of PACAP (https://pubchem.ncbi.nlm.nih.gov/compound/137699541#section=2D-Structure, accessed on 22 October 2021); (c) Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein. Image from the RCSB PDB (rcsb.org) of PDB ID 6LPB [412].
Figure 7
Figure 7
Neuropeptide Y and receptor: (a) transcription and synthesis of NPY (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of NPY (https://pubchem.ncbi.nlm.nih.gov/compound/16132350#section=2D-Structure, accessed on 22 October 2021); (c) the crystal structure of a human neuropeptide Y Y1 receptor with UR-MK299. Image from the RCSB PDB (rcsb.org) of PDB ID 5ZBQ [451].
Figure 7
Figure 7
Neuropeptide Y and receptor: (a) transcription and synthesis of NPY (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of NPY (https://pubchem.ncbi.nlm.nih.gov/compound/16132350#section=2D-Structure, accessed on 22 October 2021); (c) the crystal structure of a human neuropeptide Y Y1 receptor with UR-MK299. Image from the RCSB PDB (rcsb.org) of PDB ID 5ZBQ [451].
Figure 8
Figure 8
Neuropeptide SST and receptor: (a) transcription and synthesis of SST (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of SST (https://pubchem.ncbi.nlm.nih.gov/compound/16129706#section=2D-Structure, accessed on 22 October 2021); (c) PDZ domain from rat Shank3 bound to the C terminus of somatostatin receptor subtype 2. Image from the RCSB PDB (rcsb.org) of PDB ID 6EXJ [482].
Figure 9
Figure 9
Neuropeptide α-MSH and MC4R: (a) transcription and synthesis of α-MSH (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of α-MSH (https://pubchem.ncbi.nlm.nih.gov/compound/44273719#section=2D-Structure, accessed on 22 October 2021); (c) melanocortin receptor 4 (MC4R) Gs protein complex. Image from the RCSB PDB (rcsb.org) of PDB ID 7AUE [504].
Figure 10
Figure 10
Neuropeptide GAL: (a) transcription and synthesis of GAL (created with BioRender.com accessed on 4 November 2021); (b) 2D structure image of GAL (swine) (https://pubchem.ncbi.nlm.nih.gov/compound/16174786#section=2D-Structure, accessed on 22 October 2021).
Figure 11
Figure 11
Neuropeptide MENK and opioid receptor: (a) transcription and synthesis of MENK (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of MENK (https://pubchem.ncbi.nlm.nih.gov/compound/443363#section=2D-Structure, accessed on 22 October 2021); (c) crystal structure of the active delta opioid receptor in the complex with the small molecule agonist DPI-287. Image from the RCSB PDB (rcsb.org) of PDB ID 6PT3 [553].
Figure 12
Figure 12
Neuropeptide NT and NTS1 receptor: (a) transcription and synthesis of NT (created with BioRender.com accessed on 22 October 2021); (b) 2D structure image of NT (https://pubchem.ncbi.nlm.nih.gov/compound/25077406#section=2D-Structure, accessed on 22 October 2021); (c) high-resolution structure of thermostable agonist-bound neurotensin receptor 1 mutant without lysozyme fusion. Image from the RCSB PDB (rcsb.org) of PDB ID 4BUO [576].
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