Biology Reference
In-Depth Information
markers to distinguish NK cells of different differentiation stages. It is expected that
if meprin deficiency impairs the development of bone marrow NK cells at a given
step, the prevalence of NK cells at development stages prior to this step would be
differentially affected, with the accumulation of NK cells expressing distinct
patterns of the above markers. The studies showed that the accumulation of NK
cell in the bone marrow of meprin knockout mice occurred only to mature NK cells
with the phenotype of CD122
, but not the immature NK
precursors, implying that NK cell development from the immature to mature
forms is intact in the meprin-deficient mice (Sun, unpublished observation).
The inversely correlated distribution of monocytes and NK cells in blood and
bone marrow of dKO mice may indicate that meprins are required by these cells for
efficient egress from bone marrow to blood. Monocytes and NK cells in blood
require continuous replenishment from the bone marrow for homeostatic mainte-
nance. Egress of monocytes from bone marrow is a chemotaxis process mediated by
multiple cytokines and involving multiple steps including interaction between
cellular adhesion molecules and pericellular proteolysis of interstitial ECM
(Ebnet and Vestweber
1999
). The critical roles of chemokines in egress of bone
marrow leukocytes are exemplified by CCR-2, the receptor for monocyte chemoat-
tractant proteins (MCP). CCR-2 knockout mice exhibit the phenotype of low
monocytes in blood, with simultaneous accumulation of the same cells in bone
marrow (Serbina and Pamer
2006
; Tsou et al.
2007
). The bone marrow egress of
NK cells involves chemotaxis driven by chemokines mediated by CCR-5 and others
in response to inflammation (Inngjerdingen et al.
2001
), as well as by lysopho-
spholipid sphingosine 1-phosphate (S1P) at the steady state (Jenne et al.
2009
;
Walzer et al.
2007
). However, the defective egress of monocytes and NK cells from
bone marrow in meprin dKO mice appeared not to result from compromised
chemokine receptors. Expression of CCR-2 and CCR-5 was comparable in the
wild-type and meprin KO monocytes (Sun, unpublished observation). One possible
alternative for the mechanism involving chemotaxis is that meprin knockout mice
might have a lower level of systemic homeostatic chemokines. Consistent with this
notion, blood levels of several cytokines, including chemokine MCP-1, were lower
in meprin dKO mice than in wild-type mice (Sun, unpublished observation). The
definitive evidence for the above hypothesis would be accumulation of monocytes
and NK cells in the bone marrow of several established lines of MCP-1 knockout
mice (Lu et al.
1998
; Takahashi et al.
2009
).
The accumulation of meprin-deficient leukocytes in the bone marrow may result
from compromised capacity of the leukocyte to overcome the physical hindrance
from the interstitial ECM. ECM proteins form a continuous meshwork consisting of
distinct structural proteins including laminin, type IV collagen, entactin, and
proteoglycans in endothelial basement membrane, and type I and III febrile col-
lagens and fibronectin (FN) in the interstitial matrix (Galis et al.
1994
; Laurie et al.
1982
). This framework provides the structure critical for cell survival, develop-
ment, and locomotion (Marastoni et al.
2008
), and also poses as a barrier for
leukocyte migration (Schenkel et al.
2004
).
þ
/NK1.1
þ
/CD49b
þ
