Meprin αβ Deficiency Results in Accumulation of Peritoneal Macrophages and Hyperactive Pro-Inflammatory Cytokine Response in Mice.

Abstract 1364

Poster Board I-386

Meprin metalloproteases are abundantly expressed in kidney and intestinal epithelial cells, and have been implicated in inflammatory bowel disease. Recently, we demonstrated that meprin deficiency compromises homeostasis of monocytes and natural killer cells. However, the role(s) of meprins in the hematological system and the pathological consequences of meprin deficiency have not been fully characterized. We report here that mouse and human monocytes expressed meprins, and the expression of meprin α was down-regulated in monocyte-derived mature macrophages (Mφ). In a mouse model of septic shock induced by peritoneally injected bacterial lipopolysaccharide (LPS), mice carrying germline null mutation of both meprin α and βgenes (meprin double knockout, dKO) developed a more severe form of septic shock, characterized by deeper hypothermia, higher levels of blood nitrate/nitrites and suppressed monocytosis, in comparison to the wild-type mice. In addition, LPS-challenged meprin dKO mice exhibited a greater elevation of plasma IL-12, MCP-1, IL-6 and TNF-α, even though these pro-inflammatory cytokines were at lower levels in the dKO mice than the wild-type mice in the steady state. Furthermore, meprin dKO mice harbored a higher number of peritoneal Mφ than the wild-type mice, and thereby produced more soluble cytokines in response to ex vivo LPS stimulation. These results indicate that meprin deficiency is associated with accumulation of peritoneal Mφ, which may lead to hyperactive cytokine responses to inflammatory stimuli and result in increased susceptibility to LPS-induced septic shock.