Meprin metalloproteases modulate intestinal host response.

Meprins, zinc metalloproteases of the astacin family, are composed of two independently expressed subunits meprin alpha and beta which associate to form homo and heter-oligomers, termed meprin A and B.

Meprin isoforms are enriched in human as well as rodent intestine.

They have also been reported in kidney, leukocytes, lung and skin.

Considerable research has been conducted regarding the in vitro functions of these proteases, however the physiological roles of these proteases are unknown.

Generation of meprin beta, alpha and alphabeta knock-out mice were steps towards filling this void.

This work reports the general characterization of the meprin alpha knock-out mouse and investigates the role of meprin proteases in the mouse intestine using a model of colitis.

Several polymorphisms have been identified in the human meprin alpha gene that significantly correlate with ulcerative colitis and Crohn's disease, which make this mouse model relevant to the human pathology.

Human and rodent intestines have high but non-uniform meprin expression and hence allow one to study the contributions of different meprin isoforms.

To understand the role of meprin A, colitis was induced in wild-type and meprin alpha knock-out mice by dextran sulfate sodium administration.

Meprin alpha knock-out mice showed greater susceptibility to injury and had a phenotype of heightened inflammation as evidenced by different markers of inflammation at macroscopic as well as molecular level.

Further investigations showed a role for mucosal meprin A in the process of tissue repair.

To understand the phenotype of increased inflammation, meprin interaction with immune-mediators was studied at greater detail.

This led to the first known documentation of an in vivo interaction of meprins with an immune-mediator, interleukin-18.

Subsequent experiments using meprin alphabeta knock-out mice elucidated the contribution of meprin B in the phenotype in this model of inflammatory bowel disease.

These experiments collectively demonstrated a novel function of meprins in immuno-modulation.

This thesis furthers our knowledge about the roles of meprin metalloproteases in the rodent intestine and also elucidates the importance of proper distribution of meprin isoforms.