Role of neutrophil matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteases-1 (TIMP-1) in the killing of microorganisms.
Loading...
Date
2003
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Microorganisms may evade killing by neutrophils (PMNs) by altering signal transduction
and hence phagosome maturation. Secreted, active matrix metalloproteinases (MMPs)
appear to be required for PMN killing of pseudomonas microorganisms, via an MMP and
complement-dependent, but otherwise unknown mechanism. This also depends on
the absence of the inhibitor of MMPs, tissue inhibitor of metalloproteinases-1 (TIMP-1).
By altering their particular complement opsonin and hence the PMN complement
receptor bound, microorganism may evade killing, as not all PMN complement receptors
trigger phagosome maturation and hence killing of microorganisms. C1 inhibitor of the
classical complement cascade, required for the exposure of C1q and further assembly of
complement factors on the bacterial surface and hence binding to specific PMN
receptors, is MMP sensitive. MMP secretion may, therefore, not only facilitate the killing
of microorganisms, but inappropriate secretion, induced by pathogens, may prevent
complement assembly and killing via complement-mediated pathways. It was, therefore,
decided to assess MMP-9 and TIMP-1 secretion in the presence of C1q-opsonized
polystyrene beads and subsequently upon stimulation with pseudomonas organisms, and
explore the relationship between secretion of PMN MMPs (specifically MMP-9) and
TIMP-1 and phagocytic uptake and maturation of the PMN phagosome into a killing
body.
MMP-9 and TIMP-1 secretion was seen to occur at low levels under most conditions.
However, in the presence of serum, and hence complement, MMP-9 secretion was found
to be upregulated during uptake of C1q-coated beads. MMP-9 possibly inactivates C1
inhibitor at this stage, causing local tissue swelling (normally associated with the
inactivation of C1-inhibitor), entry of various white blood cells and further complement
into the area of infection, assisting in the extracellular killing of microorganisms. MMP secretion
may simultaneously down-regulate the activation of further PMNs via
inactivation of C1q assembly and hence phagocytic uptake and activation of PMNs. Unlike MMP-9, secretion of TIMP-1 was not upregulated by C1q receptor binding,
implying that any secreted MMP-9 may, therefore, be in excess and hence uninhibited by
TIMP-1. A distinct regulatory mechanism seems to be responsible for the release of
TIMP-1, though TIMP-1 secretion was upregulated by extracellular calcium levels,
partially contradicting previous findings which suggested that TIMP-1 was not calcium
regulated. It seems unlikely that extracellular calcium levels would be the only
mechanism by which TIMP-1 is regulated, however, and further surface receptor mediated
agonists should be explored. Levels of MMP-9 and TIMP-1 secretion in the
presence of pseudomonas microorganisms now need to be assessed to see whether these
secretion patterns are altered to favour the evasion of opsonization by C1q. Uptake of
C1q-opsonized beads was also increased by the presence of serum, possibly due to
presence of complement. MMP-9 and TIMP-1 secretion patterns still need to be
correlated with phagosomal uptake and killing of microorganisms, before their role in
killing of microorganisms becomes fully evident.
Description
Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2003.
Keywords
Neurophils., Microorganisms., Metalloproteinases--Antagonists and inhibitors., Extracellular matrix., Theses--Biochemistry.