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Calcitonin Gene-Related Peptide Regulates Specific Interferon-Stimulating Genes to Inhibit Apoptosis of Corneal
Xiaoping Hong1, Fadian Ding2,3, Ling Zhang1
1Department of Ophthalmology, The Second Affiliated Hospital of Fujian Medical University; Fujian Medical University, Quanzhou, People's Republic of China.
Purpose:
Calcitonin gene-related peptide (CGRP) has demonstrated the potential to treat dry eye disease (DED), although its mechanism is not well-understood. This study investigated the effect of CGRP on apoptosis of corneal epithelial cells in a model of DED.
Methods:
Tear samples were collected from patients with DED. Additionally, samples were collected from a rat model of DED and a CGRP overexpression human corneal epithelial (HCET) model. The concentrations of CGRP and IFN-γ in tears were detected by ELISA and analyzed in combination with clinical data. The apoptosis level of corneal epithelial cells was evaluated by Western blot, qRT-PCR, TUNEL staining, and flow cytometry. RNA-seq screening and validation of CGRP target proteins in corneal epithelial cells was also performed.
Results:
The findings of this study demonstrated a significant and positive correlation between CGRP expressed in tears of patients with DED and multiple clinical indicators of DED (P < 0.05). CGRP expression was similarly increased in the DED animal model. Exogenous CGRP peptides were observed to significantly inhibit the apoptosis of corneal tissue (P < 0.05). The CGRP overexpressing group similarly showed decreased levels of apoptosis in the corneal tissue (P < 0.05). Reduced apoptosis of corneal tissues was associated with the IFN-γ/JAK2/STAT1 pathway. RNA-seq suggested that CGRP(8-37) concurrently increased apoptosis, inhibited the expression of specific interferon-stimulating genes (SISGs), and was related to the activation of IFN-γ/JAK2/STAT1 (P < 0.05).
Conclusions:
High CGRP concentration in tears of patients with DED demonstrated a significant correlation with severity of clinical symptoms. Increased CGRP was associated with reduced apoptosis of corneal epithelial cells in an animal model of DED. Molecular evaluation identified inhibition of SISGs and activation of IFN-γ/JAK2/STAT1 as CGRP-related mechanisms potentially mediating reduced apoptosis.
Insights
Calcitonin gene-related peptide (CGRP) in tears correlates with dry eye disease (DED) severity. Increased CGRP reduces corneal epithelial cell apoptosis, potentially via the IFN-γ/JAK2/STAT1 pathway, suggesting a therapeutic role for CGRP in DED.
Area of Science:
- Ophthalmology
- Molecular Biology
- Cell Biology
Background:
- Dry eye disease (DED) is a prevalent condition affecting ocular surface health.
- Calcitonin gene-related peptide (CGRP) is being investigated for its therapeutic potential in DED.
- The precise mechanisms by which CGRP influences DED, particularly corneal epithelial cell apoptosis, remain unclear.
Purpose of the Study:
- To investigate the role of CGRP in the pathogenesis of DED.
- To determine the effect of CGRP on apoptosis of corneal epithelial cells in a DED model.
- To elucidate the molecular pathways involved in CGRP-mediated effects on corneal cells.
Main Methods:
- Collected tear samples from DED patients and established a rat model of DED.
- Utilized a human corneal epithelial cell (HCET) model with CGRP overexpression.
- Quantified CGRP and IFN-γ levels using ELISA; assessed apoptosis via Western blot, qRT-PCR, TUNEL, and flow cytometry; performed RNA-seq for target identification.
Main Results:
- A significant positive correlation was observed between tear CGRP levels and DED clinical indicators.
- CGRP levels were elevated in the DED animal model.
- Exogenous CGRP and CGRP overexpression significantly inhibited corneal epithelial cell apoptosis (P < 0.05).
- Reduced apoptosis was linked to the IFN-γ/JAK2/STAT1 pathway.
- RNA-seq indicated CGRP(8-37) increased apoptosis and inhibited interferon-stimulating genes (SISGs), implicating IFN-γ/JAK2/STAT1 activation.
Conclusions:
- Elevated CGRP in DED tears correlates with disease severity.
- CGRP demonstrates a protective effect by reducing corneal epithelial cell apoptosis in DED models.
- The protective mechanism involves the inhibition of SISGs and activation of the IFN-γ/JAK2/STAT1 pathway.
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