ADAMTS-12, a safeguard against inflammatory response

Recently, ADAMTS-12 again became the subject of conversation following a new study published in the Journal of Biological Chemistry (3). Initiated by Professor Carlos Lopez-Otin, this study aimed to determine the involvement of ADAMTS-12 in inflammatory diseases such as colitis and pancreatitis. This work necessitated the use of these new transgenic mice. “Professor Carlos Lopez-Otin and his team noticed that the mice which were deficient in ADAMTS-12 displayed more severe inflammations than their wild counterparts”, indicates Agnès Noël. In addition to these observations, the scientists demonstrated that a particularly high number of neutrophils were present in the tissues of the mutant mice.

“The neutrophils are the first cells to arrive at the lesion site. They secrete cytokines in order to mobilize other cells such as macrophages”, explains Agnès Noël. “During a normal inflammatory response the number of neutrophils becomes greatly reduced after the early stages of inflammation due to cell apoptosis. This makes it possible to avoid an exaggerated reaction”, she continues.

In order to learn more about the link between a deficiency in ADAMTS-12, an abnormally high inflammatory response and an increased number of neutrophils, the Spanish researchers carried out complementary analyses. They isolated neutrophils of human origin and placed them in in vitro cultures in the presence of the ADAMTS-12 enzyme. The result: metalloproteinase caused the apoptosis of these neutrophils. By putting together all the pieces of the puzzle, the researchers reached the conclusion that in the absence of ADAMTS-12, the neutrophils do not sufficiently move towards the apoptotic process, and therefore continue to mobilize other cells at the site of inflammation causing an exaggerated inflammatory response. Viewed in reverse this formula means: ADAMTS-12 makes a normal controlled inflammatory response possible by causing the death of the neutrophils after the first phase of this process.

A new interest in metalloproteinases

 “It is interesting to note that knock-out mice which were created thanks to a collaboration in the context of cancer research can also be used in other research areas such as the study of the immune response”, explains Agnès Noël.  For this reason, the precious mice model made it possible to identify ADAMTS-12 as an important actor both in inflammatory response and asthmatic pathology as well as in the case of colitis and pancreatitis. It also made it possible to show that this enzyme plays a role in the regulation of the numbers of cells involved in this process.  “Understanding what are the mediators of the inflammatory response and how they inhibit or increase it is vital in order to better understand the mechanisms and therefore be able to act on these mechanisms”, she concludes.

Known up to now for their role in the degradation of extracellular matrix components, the metalloproteinases -represented here by ADAMTS-12 – have shown that they had other strings to their bow. The knock-out mice created by the Belgo-Spanish collaboration will perhaps still prove useful for discovering even more!

(3) Angela Moncada-Pazos, Alvaro J. Obaya, María Llamazares, Ritva Heljasvaara, María F. Suárez, Enrique Colado, Agnès Noël, Santiago Cal and Carlos López-Otín. ADAMTS-12 Metalloprotease Is Necessary for Normal Inflammatory Response. J Biol Chem. 2012 Nov 16;287(47):39554-63. doi: 10.1074/jbc.M112.408625. Epub 2012 Sep 27.