Meprins are metalloproteases first discovered in kidney and intestinal epithelial cells, and have been implicated in autoimmune diseases. We have shown that homeostasis of monocytes is compromised in meprin alpha/beta null (alpha-/-/beta-/-) mice. However, the mechanisms responsible for the involvement of meprins in the immune and hematological system remain uncharacterized. We report here that human monocytes expressed meprins, and the expression of meprins was down-regulated in mature macrophages and dendritic cells but not their immature counterparts. We further show that bone marrow monocytes and peritoneal macrophages from meprin-deficient mice had decreased efficiency in migration through extracellular matrix (ECM) compared to those from the wild-type mice in Boyden assays without marked defects in cell mobility in the absence of ECM. In a sepsis shock model, meprin-deficient mice exhibited more severe hypothermia than the wild-type mice in response to peritoneally injected lipopolysaccharide (LPS), and the prevalence of blood monocytes in the merpin-deficient mice were only 25% of that in the wild-type mice, with compensatory increase of lymphocytes. While meprin-deficient mice in the steady state had moderately lower blood levels of IL-12, MCP-1 and IL-6 than the wild-type mice, LPS-challenged meprin-deficient mice exhibited a drastic elevation of the above inflammatory cytokines in comparison to the wild-type mice, with comparable blood concentrations of IFN-gamma and IL-10 between the two mice. These results indicate that meprin metalloproteases are required for efficient trans-ECM migration of monocytes, and meprin deficiency is associated with defects in monocyte functions which have pathological consequences.