Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus
Keratoconus (KC) is a corneal disorder whose etiology shares a close relationship with Lactoferrin (LTF) dysregulation and Toll-like Receptors 2 (TLR2) overexpression. This study shows how these two important biomarkers are clinically and molecularly interrelated, increasing knowledge about KC patho...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/20/12350 |
| _version_ | 1797431552508952576 |
|---|---|
| author | Uxía Regueiro Maite López-López Rubén Varela-Fernández Tomás Sobrino Elio Diez-Feijoo Isabel Lema |
| author_facet | Uxía Regueiro Maite López-López Rubén Varela-Fernández Tomás Sobrino Elio Diez-Feijoo Isabel Lema |
| author_sort | Uxía Regueiro |
| collection | DOAJ |
| description | Keratoconus (KC) is a corneal disorder whose etiology shares a close relationship with Lactoferrin (LTF) dysregulation and Toll-like Receptors 2 (TLR2) overexpression. This study shows how these two important biomarkers are clinically and molecularly interrelated, increasing knowledge about KC pathophysiology, and opening the door to future therapies. In this prospective clinical study, serum and tear LTF concentrations were quantified in 90 KC patients and 60 controls. A correlation analysis with multiple blood and tear immunoinflammatory mediators, and KC-associated tomographic parameters, was performed. An in vitro study using HEK-Blue<sup>TM</sup>hTLR2 cell cultures was also conducted to determine the expression and functionality of TLR2 under the influence of LTF treatment. As a result, a LTF decreased was observed in KC patients compared to controls (<i>p</i> < 0.0001), evidencing the strong correlation with TLR2 overexpression at systemic and ocular surface level, with inflammatory mediator upregulation and with KC severity. In stimulated cell cultures, TLR2 expression was decreased using 2 mg/mL of LTF. The levels of secreted embryonic alkaline phosphatase (SEAP) and interleukin-8 (IL-8) were also reduced in supernatants after LTF treatment. As conclusions, the dysregulation of LTF and TLR2 in the ocular surface of KC patients contributes to KC severity by maintaining a detrimental chronic immune–inflammatory state. The immunomodulatory properties of LTF on TLR2 expression suggest its potential as a therapeutic approach for KC. |
| first_indexed | 2024-03-09T09:46:48Z |
| format | Article |
| id | doaj.art-5836adf6e2674b5db9249895a09f4f44 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T09:46:48Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5836adf6e2674b5db9249895a09f4f442023-12-02T00:32:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201235010.3390/ijms232012350Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for KeratoconusUxía Regueiro0Maite López-López1Rubén Varela-Fernández2Tomás Sobrino3Elio Diez-Feijoo4Isabel Lema5Corneal Neurodegeneration Group (RENOIR), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, SpainCorneal Neurodegeneration Group (RENOIR), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, SpainCorneal Neurodegeneration Group (RENOIR), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, SpainNeuroAging Laboratory (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, SpainCorneal Neurodegeneration Group (RENOIR), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, SpainCorneal Neurodegeneration Group (RENOIR), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, SpainKeratoconus (KC) is a corneal disorder whose etiology shares a close relationship with Lactoferrin (LTF) dysregulation and Toll-like Receptors 2 (TLR2) overexpression. This study shows how these two important biomarkers are clinically and molecularly interrelated, increasing knowledge about KC pathophysiology, and opening the door to future therapies. In this prospective clinical study, serum and tear LTF concentrations were quantified in 90 KC patients and 60 controls. A correlation analysis with multiple blood and tear immunoinflammatory mediators, and KC-associated tomographic parameters, was performed. An in vitro study using HEK-Blue<sup>TM</sup>hTLR2 cell cultures was also conducted to determine the expression and functionality of TLR2 under the influence of LTF treatment. As a result, a LTF decreased was observed in KC patients compared to controls (<i>p</i> < 0.0001), evidencing the strong correlation with TLR2 overexpression at systemic and ocular surface level, with inflammatory mediator upregulation and with KC severity. In stimulated cell cultures, TLR2 expression was decreased using 2 mg/mL of LTF. The levels of secreted embryonic alkaline phosphatase (SEAP) and interleukin-8 (IL-8) were also reduced in supernatants after LTF treatment. As conclusions, the dysregulation of LTF and TLR2 in the ocular surface of KC patients contributes to KC severity by maintaining a detrimental chronic immune–inflammatory state. The immunomodulatory properties of LTF on TLR2 expression suggest its potential as a therapeutic approach for KC.https://www.mdpi.com/1422-0067/23/20/12350keratoconuslactoferrinocular surface disordersToll-like receptors |
| spellingShingle | Uxía Regueiro Maite López-López Rubén Varela-Fernández Tomás Sobrino Elio Diez-Feijoo Isabel Lema Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus International Journal of Molecular Sciences keratoconus lactoferrin ocular surface disorders Toll-like receptors |
| title | Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus |
| title_full | Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus |
| title_fullStr | Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus |
| title_full_unstemmed | Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus |
| title_short | Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus |
| title_sort | immunomodulatory effect of human lactoferrin on toll like receptors 2 expression as therapeutic approach for keratoconus |
| topic | keratoconus lactoferrin ocular surface disorders Toll-like receptors |
| url | https://www.mdpi.com/1422-0067/23/20/12350 |
| work_keys_str_mv | AT uxiaregueiro immunomodulatoryeffectofhumanlactoferrinontolllikereceptors2expressionastherapeuticapproachforkeratoconus AT maitelopezlopez immunomodulatoryeffectofhumanlactoferrinontolllikereceptors2expressionastherapeuticapproachforkeratoconus AT rubenvarelafernandez immunomodulatoryeffectofhumanlactoferrinontolllikereceptors2expressionastherapeuticapproachforkeratoconus AT tomassobrino immunomodulatoryeffectofhumanlactoferrinontolllikereceptors2expressionastherapeuticapproachforkeratoconus AT eliodiezfeijoo immunomodulatoryeffectofhumanlactoferrinontolllikereceptors2expressionastherapeuticapproachforkeratoconus AT isabellema immunomodulatoryeffectofhumanlactoferrinontolllikereceptors2expressionastherapeuticapproachforkeratoconus |