Disruption of the meprin α and β genes in mice alters homeostasis of monocytes and natural killer cells

Abstract

Meprin metalloproteases are implicated in inflammatory bowel disease, which involves dysfunction of immune cells. However, the roles of meprins in the immune and hematological system remain uncharacterized. In this report, we demonstrate that meprins were expressed in the hematological system, and meprin alpha/beta null (alpha -/-/beta -/-) mice had decreased prevalence of resident monocytes (R-MC) and natural killer (NK) cells in blood, with a concomitant accumulation of inflammatory monocytes (I-MC) and NK cells in bone marrow. In contrast, T and B lymphocytes were not affected by meprin deficiency. In response to acute inflammation induced by intraperitoneal injection of thioglycollate, meprin-deficient mice exhibited higher body temperature than the wildtype mice, which was correlated with accumulation of I-MC but persistent low prevalence of NK cells in blood. These results indicate that meprin metalloproteases play important roles in the homeostasis of monocytes and NK cells, and possibly are involved in egress of these two type cells from bone marrow and homing to the periphery. Our findings are the first report to demonstrate that metalloproteases affect homeostasis of leukocytes, which have important implications for understanding physiology of and pathogenesis in the hematological system.

Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease

“…The absence of meprin ␣ and of meprin ␤ in the dKO mice was further confirmed by Western analyses (Fig. 1, G and H), in addition to both Southern analysis as well as PCR from tail biopsies (37).…”

“…Urine creatinine was lower only in male mice whereas plasma albumin was elevated in both male and female mice, perhaps indicating a genetically determined difference in the filtration or reabsorption of tissue fluids and blood components (27). There is also evidence that leukocytes behave differently in dKO mice compared with WT mice (37). Monocytes and natural killer cells have been shown to express meprins, and their movement from bone marrow to blood appears to be affected by meprin expression.…”

“…In addition, they are found in human intestinal lamina propria leukocytes and mouse mesenteric lymph nodes in the presence as well as absence of intestinal inflammation (14,29,30). Meprin ␣ and meprin ␤ mRNA are also expressed in the mononuclear cell lineages in both human and mouse peripheral blood (37). The evolutionarily related meprin subunits are encoded on different chromosomes (␣ on human chromosome 6 and mouse chromosome 17; ␤ on human and mouse chromosome 18) and share ϳ40% amino acid identity (11,18,19,25,26).…”

Isoform-specific interactions between meprin metalloproteases and the catalytic subunit of protein kinase A: significance in acute and chronic kidney injury

“…Meprin interactions with the PKA pathway could thus play a role in the response to insults that cause renal injury. In addition to modulating injury in tubular cells where meprins are most abundant, expression of meprins in leukocytes (48) and podocytes (33) suggests that meprins could modulate ECM metabolism in renal glomeruli and may thus play a role in the ECM buildup and fibrosis associated with diabetic nephropathy. Indeed, while PKA-mediated signaling occurs in many cell types, the downstream modulators of the PKA-transforming growth factor (TGF)-␤1-induced response are cell-type specific and depend on the cellular environment.…”

“…The mouse PKA C␤2 variant is highly expressed in lymphoid tissue (13), suggesting a role in the immune response. This interaction is relevant because expression of meprins has been documented in monocytes and macrophages (48), making a case for meprin modulation of the immune response. Meprins were also shown to impact infiltration of leukocytes and cleave proinflammatory cytokines such as pro-IL-18.…”