Impact of cationic host defence peptide LL-37 on human neutrophil death and inflammatory responses
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Li2011.doc (28.84Mb)
Date
05/07/2011Author
Li, Hsin-Ni
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Abstract
Cathelicidins are cationic host defence peptides (CHDP) with essential roles in
the innate defence system. These peptides have antimicrobial potential and the
capacity to modulate innate immunity and inflammatory processes. Neutrophils
(PMN) are the main reservoir of cathelicidins and play key roles in first line
defence against infection. The appropriate regulation of PMN function, death, and
clearance is critical to innate immunity, and the efferocytosis of apoptotic PMN, in
contrast to necrotic cells, is proposed to promote the resolution of inflammation. In
this thesis I demonstrate that the human cathelicidin LL-37 rapidly induced
secondary necrosis of apoptotic human PMN and identify the essential C-terminal
region of LL-37 required for this activity. In addition to the induction of secondary
necrosis, higher concentrations of LL-37 also promoted PMN granule contents
release. LL-37-induced secondary necrosis did not affect PMN ingestion by human
monocyte-derived macrophages and, in contrast to expectation, was not proinflammatory.
Interestingly, the anti-inflammatory effects of apoptotic PMN on
activated macrophages were retained and even potentiated where LL-37-mediated
secondary necrosis induced anti-inflammatory granule content release. Consistent
with the results of in vitro studies, in vivo murine sterile peritonitis model revealed
the same phenomenon: LL-37-induced secondary necrosis diminished
inflammatory responses with decreased PMN influx. I also present data on LL-37-
mediated modulation of innate immune effector cell cytokines responses to
inflammatory signals. I propose that during acute inflammation LL-37 can
modulate innate immune responses through its activity on cytokine production, and
that LL-37-mediated secondary necrosis of apoptotic PMN has anti-inflammatory effects, but may also mediate host damage by promoting the release of potentially
harmful intracellular contents under chronic or dysregulated conditions.