Biology Reference
In-Depth Information
Multiple proteases have been implicated in leukocyte migration. MMP-9 effi-
ciently degrades ECM proteins laminin and collagen IV in vitro and is involved
in migration of Langerhans cells and dendritic cells (DC) in the absence of ECM
(Baratelli et al.
2004
; Ratzinger et al.
2002
; Tojo et al.
1999
; Xie et al.
1998
). The
degradation of fibronectin by MMP-14 (TM1-MMP) has been correlated with
monocyte migration (Matias-Roman et al.
2005
), and MMP-12 null mice exhibit
delayed recruitment of macrophages into subcutaneous sponge (Shipley et al.
1996
).
In addition to ECM degradation, MMPs are well established for transmigration of
monocytes through endothelial barriers by interacting with intracellular adhesion
molecule-1 (ICAM-1) (Matias-Roman et al.
2005
; Sithu et al.
2007
) and by disrupt-
ing the tight junctions formed by occludin molecules (Reijerkerk et al.
2006
). In
addition, plasminogen/plasmin-mediated pericellular proteolysis play critical roles
for migration of blood monocytes to inflammation sites (Gong
2008
; Wygrecka et al.
2009
), which may work synergically with MMP-9 (Gong
2008
). There is evidence
that meprin is involved in the trans-ECM migration of leukocytes. Ample in vitro
biochemical studies showed that meprins are capable of degrading ECM proteins
(Bylander et al.
2007
; Kaushal et al.
1994
; Kruse et al.
2004
). Furthermore, in vitro
studies revealed that macrophages frommeprin
KOmice are defective in the trans-
ECM migration (Crisman et al.
2004
) (Fig.
4.9
), and human breast cancer cells
treated with the meprin inhibitor actinonin are less invasive (Matters et al.
2005
).
The mechanisms responsible for the abnormal hematology in meprin-deficient
mice remain to be determined; however, meprin deficiency appears pathologically
relevant, at least in animal models. Indeed, mice deficient in both
b
meprins
exhibited overactive febrile reactions in the model of thioglycollate-induced peri-
tonitis, implying meprins' role in inflammation process (Sun et al.
2009
). In
addition, meprin
and
a
b
KO mice are predisposed to colitis with systemic alterations in
cytokine responses to intestinal stimulation by DSS (Banerjee et al.
2009
), a model
for IBD. This is consistent with the critical roles of monocytes in the innate
immunity as well as in adaptive immune responses, and it is reasonable to predict
that meprin deficiency is associated with compromised immunity in human patho-
logical conditions yet to be recognized.
a
4.6 Meprins Have Been Implicated in a Number of Diseases
Meprins have been implicated in several inflammatory diseases and in cancer. The
expression of meprins in several types of cancer cells (intestinal, breast, bone) has
implicated these proteases in the growth and metastases of tumors (Bond et al.
2005
; Matters et al.
2005
). The targets for meprins in cancer cells, as for immune
system cells, are likely cytokines, adhesion proteins, and ECM proteins, and this
enables mobility of these cells to secondary sites.
The meprin KO mouse studies support the contention that meprins have a
functional role in inflammatory diseases. In the case of experimental IBD, a lack
of meprin
increases the severity of this disease. Interestingly, there is also strong
a
