A molecular mechanism by which immune cells regulate inflammatory responses, which are often associated with diseases such as sepsis, is revealed in a report published online in Nature Immunology this week.

Rama Mallampalli and colleagues find that a molecule called Fbxl2 is present within certain immune cells and this potently arrests the ability of cells to produce inflammatory mediators. However, when cells are exposed to microbial products they engage a second molecule called Fbxo3, which degrades Fbxl2 and thereby allows activation of the cell. The team goes on to synthesize a drug which blocks Fbxo3, thereby maintaining high levels of Fbxl2 that keep cells in an inactive state. This was shown to be beneficial in various mouse models of inflammatory disease. Alterations in the level and function of Fbxl2 and Fbxo3 were found associated with human sepsis and the team note that a natural human mutation in Fbxo3 resulted in weaker inflammatory responses by immune cells.

This study demonstrates an important pathway regulating inflammation in both humans and mice and offers useful molecular insights into how these could be therapeutically targeted.