Cutting the head off chemokines

Chemokines are small secreted proteins that attract leukocyte migration. Chemokines play essential roles in the normal immune response against invading pathogens. Unfortunately, in an unregulated state they can also mediate abnormal leukocyte infiltration in ARDS, postinfarction damage, and multiple auto-immune diseases. In addition, chemokines or their receptors have also been subverted for nefarious purposes by viruses as diverse as KHSV and HIV.

Since abnormal expression of chemokines can produce so many diseases of leukocyte tissue destruction, a major issue in chemokine research is how the effect of chemokines is down-regulated. Such down-regulation after proper leukocyte tissue infiltration is important to prevent inappropriate flooding of adjacent normal tissue with activated leukocytes.

It has recently been shown that some chemokines can have their amino terminus cleaved off by extracellular proteases. Since the amino terminus mediates receptor activation, this creates truncated chemokines that can bind to but not activate their cognate receptors. Specific mechanisms for this have not been completely defined.

The report by McQuibban and colleagues in this issue (page 1160) provides a fascinating insight into the down-regulation of one subset of chemokines, the monocyte chemotactic proteins MCP-1, MCP-2, MCP-3, and MCP-4. They found that several matrix metalloproteinases (MMPs), which are secreted during the inflammatory response, can specifically cleave off the amino termini of many of the MCPs. Intriguingly, MMP-2, secreted and activated late in the inflammatory response, uniquely cleaves MCP-3. This cleaved MCP-3 functions as a potent antagonist to macrophage chemotaxis both in vitro and in vivo. Indeed, cleaved MCP-3 not only had the capability of blocking the initiation of an in vivo inflammatory response but also completely abrogated prior inflammation.

These data have significant implications. First, this study provides a detailed mechanism by which chemokine activity is immediately down-regulated at a specific stage in the inflammatory response. Second, the cleaved MCP-3 may be clinically useful in preventing tissue damage in septic shock, viral infections, ARDS, or a number of diseases of abnormal macrophage infiltration. Third, since MMPs are important in many types of tissue remodeling from embryonic development to wound healing to cancer metastasis, it is tempting to speculate that this mechanism may be important in terminating local macrophage function during such tissue remodeling.