Study summary · research use only
Human cathelicidin LL-37 rapidly disrupted colonic epithelial integrity
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study used human colonic epithelial (T84) cells and murine rectal epithelial (CMT-93) cells to examine how the human cathelicidin peptide LL-37 affects intestinal epithelial permeability. Direct stimulation of T84 cells with LL-37 produced a rapid and transient increase in permeability, associated with degradation of the tight junction proteins occludin and claudin-2 via endocytosis and lysosomal degradation. Murine cathelicidin (CRAMP) did not alter T84 cell permeability, but LL-37 degraded tight junction proteins in CMT-93 cells and increased permeability and tight junction degradation when combined with infection by the pathogen Citrobacter rodentium (C. rodentium); the number of C. rodentium colonizing CMT-93 cells was not strongly affected by LL-37. The authors describe these findings as pointing to a role for cathelicidin in modulating the epithelial barrier.
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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