A novel peptide derived from the mannose binding lectin inhibits LPS‐activated TLR4/NF‐κB signaling and suppresses ocular inflammation

Author:

Lu Yi12345,Wang Ruonan12345,Jin Huiyi12345,Xie Jiamin12345,Gu Qing12345,Yang Xiaolu12345ORCID

Affiliation:

1. Department of Ophthalmology, Shanghai General Hospital Shanghai JiaoTong University Shanghai China

2. Shanghai Key Laboratory of Ocular Fundus Disease Shanghai China

3. Shanghai Engineering Center for Visual Science and Photomedicine Shanghai China

4. National Clinical Research Center for Eye Diseases Shanghai China

5. Shanghai Engineering Center of Precise Diagnosis and Treatment of Eye Diseases Shanghai China

Abstract

AbstractUveitis is a major cause of vision impairment worldwide. Current treatments have limited effectiveness but severe complications. Mannose binding lectin (MBL) is an important protein of the innate immune system that binds to TLR4 and suppresses LPS‐induced inflammatory cytokine secretion. MBL‐mediated inhibition of inflammation via the TLR4 pathway and MBL‐derived peptides might be a potential therapeutics. In this study, we designed a novel MBL‐derived peptide, WP‐17, targeting TLR4. Bioinformatics analysis was conducted for the sequence, structure and biological properties of WP‐17. The binding of WP‐17 to THP‐1 cells was analyzed using flow cytometry. Signaling molecules were analyzed by western blotting, and activation of NF‐κB was measured by immunofluorescence‐histochemical analysis. Effects of WP‐17 were studied in vitro using LPS‐stimulated THP‐1 cells and in vivo in endotoxin‐induced uveitis (EIU). Our results showed that WP‐17 could bind to TLR4 expressed on macrophages, thus downregulating the expression levels of MyD88, IRAK‐4, and TRAF‐6, and inhibiting the downstream NF‐kB signaling pathway and LPS‐induced expression of TNF‐α and IL‐6 in THP‐1 cells. Moreover, in EIU rats, intravitreal pretreatment with WP‐17 demonstrated significant inhibitory effects on ocular inflammation, attenuating the clinical and histopathological manifestations of uveitis, reducing protein leakage and cell infiltration into the aqueous humor, and suppressing TNF‐α and IL‐6 production in ocular tissues. In summary, our study provides the first evidence of a novel MBL‐derived peptide that suppressed activation of the NF‐кB pathway by targeting TLR4. The peptide effectively inhibited rat uveitis and may be a promising candidate for the management of ocular inflammatory diseases.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cell Biology,General Medicine

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