Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus

• Published in: International journal of molecular sciences 2022-10, Vol.23 (20), p.12350
• Main Authors: Regueiro, Uxía, López-López, Maite, Varela-Fernández, Rubén, Sobrino, Tomás, Diez-Feijoo, Elio, Lema, Isabel
• Format: Article
• Language: English
• Subjects: Age; Alkaline phosphatase; Alkaline Phosphatase - metabolism; Binding sites; Biomarkers - metabolism; Cell culture; Cornea; Correlation analysis; Disease; Embryos; Etiology; Flow cytometry; Glycoproteins; Humans; Immune system; Immunomodulation; Inflammation; Interleukin 8; Interleukin-8 - metabolism; Keratoconus; Keratoconus - drug therapy; Keratoconus - metabolism; Lactoferrin; Lactoferrin - metabolism; Neutrophils; ocular surface disorders; Patients; Prospective Studies; Proteins; TLR2 protein; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-like receptors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232012350

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-BlueTMhTLR2 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 (p < 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.