Human cathelicidin LL-37 rapidly disrupted colonic epithelial integrity.

IF 2.8 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Biomembranes Pub Date : 2025-01-19 DOI:10.1016/j.bbamem.2025.184410
Geeta Kilari, Jacquelyn Tran, Graham A D Blyth, Eduardo R Cobo
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Abstract

The intestinal barrier, held together by epithelial cells and intercellular tight junction (TJ) proteins, prevents the penetration of microbial pathogens. Concurrently, intestinal epithelial cells secrete antimicrobial peptides, including cathelicidin. Cathelicidin has direct antibacterial and immunomodulatory functions, although its role in intestinal integrity remains elusive. In this study, we demonstrate that direct stimulation of human colonic epithelial (T84) cells with human cathelicidin, LL-37, resulted in a rapid and transient increase in epithelial cell permeability. This increased permeability was associated with the TJ proteins occludin and claudin-2 degradation, mediated by these specific proteins' endocytosis and lysosomal degradation. While murine cathelicidin (CRAMP) failed to modify T84 cell permeability, LL-37 degraded TJ proteins in murine rectal epithelial (CMT-93) cells. The stimulus of (CMT-93) cells with LL-37 aggravated the cell permeability and furthered TJ degradation provoked by the intestinal pathogen, attaching/effacing (A/E) Citrobacter rodentium (C. rodentium). The number of C. rodentium that colonized CMT-93 cells was not severely impacted by the presence of LL-37. While a temporary disruption of tight junctions by LL-37 may lead to a 'leaky gut,' this study demonstrates that LL-37 increases epithelial cell permeability by degrading TJ proteins occludin and claudin-2 through endocytosis and lysosomal degradation. These immunomodulatory actions occurring at concentrations lower than those microbicidal uncover a new guise for cathelicidin modulating the epithelial barrier against A/E pathogens. Recognizing native cathelicidin's functions in a specified disease setting (e.g., colitis) will help establish it as an anti-infectious immunomodulator.

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人cathelicidin LL-37迅速破坏结肠上皮的完整性。
肠道屏障由上皮细胞和细胞间紧密连接(TJ)蛋白结合在一起,防止微生物病原体的渗透。同时,肠上皮细胞分泌抗菌肽,包括抗菌肽。抗菌肽具有直接的抗菌和免疫调节功能,但其在肠道完整性中的作用尚不明确。在这项研究中,我们证明了用人cathelicidin LL-37直接刺激人结肠上皮细胞(T84),导致上皮细胞通透性快速和短暂的增加。这种通透性的增加与TJ蛋白occludin和claudin-2的降解有关,这是由这些特定蛋白的内吞作用和溶酶体降解介导的。虽然小鼠cathelicidin (CRAMP)不能改变T84细胞的通透性,但LL-37可以降解小鼠直肠上皮(CMT-93)细胞中的TJ蛋白。LL-37对(CMT-93)细胞的刺激增加了细胞的通透性,促进了肠道病原菌(A/E) Citrobacter rodentium (C. rodentium)引起的TJ降解。LL-37的存在对CMT-93细胞的定植数量影响不大。虽然LL-37暂时破坏紧密连接可能导致“漏肠”,但本研究表明LL-37通过内吞作用和溶酶体降解TJ蛋白occludin和cludin -2,从而增加上皮细胞的通透性。这些免疫调节作用在浓度低于杀微生物剂时发生,揭示了抗菌肽调节上皮屏障对抗a /E病原体的新伪装。认识到天然抗菌肽在特定疾病(如结肠炎)中的功能将有助于确定其作为抗感染免疫调节剂的作用。
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来源期刊
Biochimica et biophysica acta. Biomembranes
Biochimica et biophysica acta. Biomembranes 生物-生化与分子生物学
CiteScore
8.20
自引率
5.90%
发文量
175
审稿时长
2.3 months
期刊介绍: BBA Biomembranes has its main focus on membrane structure, function and biomolecular organization, membrane proteins, receptors, channels and anchors, fluidity and composition, model membranes and liposomes, membrane surface studies and ligand interactions, transport studies, and membrane dynamics.
期刊最新文献
Tuning expression of GPCRs for the secretory pathway in the baculovirus-insect cell expression system. Phase-separated cationic giant unilamellar vesicles as templates for the polymerization of tetraethyl orthosilicate (TEOS). Identification of a sorting motif for Tspan3 to MHCII compartments in human B cells. Characterization of intact FeoB in a lipid bilayer using styrene-maleic acid (SMA) copolymers. Human cathelicidin LL-37 rapidly disrupted colonic epithelial integrity.
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