Consequences of Elastolysis - Extracellular Matrix Degradation - page 238

and macrophages express both cathepsins S and K in this context. Decreased elastin
breaks have been documented for both CatS / and CatK / mice in this context
and likely impact macrophage accumulation. Additionally, there may be more
sophisticated and nonelastolytic functions for these enzymes in atherosclerotic
disease. For a more detailed review of cysteine cathepsins, see Chap. 2.
9.6 Nonelastolytic Contributions of Elastases
Matrix degrading enzymes have traditionally been named for the substrates that
they degrade (i.e., collagenases, elastases, gelatinases, etc.). The fact that an
enzyme can degrade a given substrate in vitro demonstrates what the enzyme can
do, but not necessarily what it does do, in vivo . Elastin is such an inert substrate that
elastolysis is an important biological function for essentially all elastases. On the
other hand, one could assume that because elastases are such good enzymes, they
will possess very broad substrate specificities and thus play important roles inde-
pendent of elastin. Indeed, novel, nonelastolytic roles continue to emerge for
elastases in important aspects of biology including host interactions with invading
microbes and tumors.
9.6.1 Antimicrobial Properties of Elastases
Host defense against invading microorganisms is an elaborate process involving
several different cell types that make up the innate and adaptive immune system.
Macrophages and neutrophils, both of which possess elastolytic enzymes, represent
the first line of defense (innate) against infection. Macrophages have been long
known to clear invading microorganisms during the initial stages of infection
(Green and Kass 1964 ) but the means by which they do so was poorly understood.
Macrophages possess some defensin-like antimicrobial peptides and reactive
nitrogen species that display antimicrobial properties (Biggar and Sturgess 1977 ;
Hiemstra et al. 1993 ; Ganz 1999 ). It has recently been shown that macrophage
elastase (MMP12) also significantly contributes to the microbicidal properties of
macrophages (Houghton et al. 2009 ).
MMP12 / mice display increased mortality when challenged with bacteria at
macrophage-rich portals of entry, such as the peritoneum and lung. Using macro-
phage-killing assays, we were able to demonstrate that MMP12 / macrophages
were able to phagocytose bacteria normally, but were unable to kill them. Additional
studies revealed that MMP12 is directly bactericidal to both Gram-negative ( E. coli )
and Gram-positive ( S. aureus ) bacteria. MMP12 disrupts bacterial membrane integ-
rity resulting in bacterial cell lysis and death. Interestingly, MMP12 does not require
its catalytic domain to kill bacteria. All of the bactericidal activity of MMP12 resides
within a 20-residue sequence (SR-20) located in the carboxy-terminal domain (CTD),