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Effects of the host defense peptide LL-37 on human cells : Immunomodulation and cytotoxicity

Bodahl, Sara LU orcid (2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
The human host defense peptide LL-37 has an essential role in the first line of defense against invading pathogens. This cathelicidin is mainly produced by immune cells and epithelial cells aligning the mucosal areas and is normally upregulated upon infection and inflammation. LL-37 displays direct antimicrobial activity against a variety of pathogens, but also modulates the immune responses by acting as a chemoattractant, influencing the production of inflammatory mediators and by affecting immune receptor signaling. Abnormally high local levels of LL-37 have been linked to inflammatory diseases, such as psoriasis, atherosclerosis, periodontitis and asthma. However, little is known about the role of LL-37 in the development and... (More)
The human host defense peptide LL-37 has an essential role in the first line of defense against invading pathogens. This cathelicidin is mainly produced by immune cells and epithelial cells aligning the mucosal areas and is normally upregulated upon infection and inflammation. LL-37 displays direct antimicrobial activity against a variety of pathogens, but also modulates the immune responses by acting as a chemoattractant, influencing the production of inflammatory mediators and by affecting immune receptor signaling. Abnormally high local levels of LL-37 have been linked to inflammatory diseases, such as psoriasis, atherosclerosis, periodontitis and asthma. However, little is known about the role of LL-37 in the development and progression of inflammatory and autoimmune diseases and more research is needed to clarify and establish how LL-37 mediates host cell functions in these conditions.
In this thesis we have studied LL-37-induced cell toxicity, cell membrane permeability and immune receptor signaling in several types of human cells. We show that LL-37 reduces cell viability in a dose-dependent manner and permeabilizes the cell membranes in all human cell types studied. Interestingly, we demonstrate that LL-37 reduces the cell viability and generates cell membrane permeabilization in osteoblast-like cells even though LL-37 import via clathrin-mediated endocytosis is prevented. In mast cells, LL-37-induced cell membrane permeabilization results in release of both cytosolic and nucleic components, indicating that LL-37 permeabilizes cellular compartments such as the nucleus. Furthermore, we show that LL-37 influences TLR3 signaling in both coronary artery smooth muscle cells and bronchial epithelial cells. More specifically, LL-37 enhances viral dsRNA signaling on TLR3, resulting in upregulation of TLR3 expression and downstream pro-inflammatory signaling that involves the transcription factor NF-κB. Finally, we show that LL-37 induces an increased import of dsRNA in bronchial epithelial cells, suggesting that this mechanism of action is associated with upregulated expression of TLR3.
Overall, the work in this thesis provides new insights on underlying mechanisms behind LL-37-induced host cytotoxicity and cell membrane permeability and proposes a novel LL-37-driven pro-inflammatory mechanism of action involving potentiation of dsRNA-stimulated TLR3 expression and signaling
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Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Docent Pütsep, Katrin, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
LL-37, Host defense peptides, Cathelicidin, Inflammation, Cytotoxicity, TLR3, Poly I:C
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2022:53
pages
69 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/65485554261
defense date
2020-05-13 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-214-4
language
English
LU publication?
yes
id
a97ed58a-d956-4da1-b96c-816bf088f629
date added to LUP
2022-04-19 13:09:50
date last changed
2022-04-27 16:58:00
@phdthesis{a97ed58a-d956-4da1-b96c-816bf088f629,
  abstract     = {{The human host defense peptide LL-37 has an essential role in the first line of defense against invading pathogens. This cathelicidin is mainly produced by immune cells and epithelial cells aligning the mucosal areas and is normally upregulated upon infection and inflammation. LL-37 displays direct antimicrobial activity against a variety of pathogens, but also modulates the immune responses by acting as a chemoattractant, influencing the production of inflammatory mediators and by affecting immune receptor signaling. Abnormally high local levels of LL-37 have been linked to inflammatory diseases, such as psoriasis, atherosclerosis, periodontitis and asthma. However, little is known about the role of LL-37 in the development and progression of inflammatory and autoimmune diseases and more research is needed to clarify and establish how LL-37 mediates host cell functions in these conditions. <br/>In this thesis we have studied LL-37-induced cell toxicity, cell membrane permeability and immune receptor signaling in several types of human cells. We show that LL-37 reduces cell viability in a dose-dependent manner and permeabilizes the cell membranes in all human cell types studied. Interestingly, we demonstrate that LL-37 reduces the cell viability and generates cell membrane permeabilization in osteoblast-like cells even though LL-37 import via clathrin-mediated endocytosis is prevented. In mast cells, LL-37-induced cell membrane permeabilization results in release of both cytosolic and nucleic components, indicating that LL-37 permeabilizes cellular compartments such as the nucleus. Furthermore, we show that LL-37 influences TLR3 signaling in both coronary artery smooth muscle cells and bronchial epithelial cells. More specifically, LL-37 enhances viral dsRNA signaling on TLR3, resulting in upregulation of TLR3 expression and downstream pro-inflammatory signaling that involves the transcription factor NF-κB. Finally, we show that LL-37 induces an increased import of dsRNA in bronchial epithelial cells, suggesting that this mechanism of action is associated with upregulated expression of TLR3. <br/>Overall, the work in this thesis provides new insights on underlying mechanisms behind LL-37-induced host cytotoxicity and cell membrane permeability and proposes a novel LL-37-driven pro-inflammatory mechanism of action involving potentiation of dsRNA-stimulated TLR3 expression and signaling<br/>}},
  author       = {{Bodahl, Sara}},
  isbn         = {{978-91-8021-214-4}},
  issn         = {{1652-8220}},
  keywords     = {{LL-37; Host defense peptides; Cathelicidin; Inflammation; Cytotoxicity; TLR3; Poly I:C}},
  language     = {{eng}},
  number       = {{2022:53}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Effects of the host defense peptide LL-37 on human cells : Immunomodulation and cytotoxicity}},
  url          = {{https://lup.lub.lu.se/search/files/116946439/Sara_Bodahl_for_web.pdf}},
  year         = {{2022}},
}