A citrulline-containing IL-8 isoform fails to recruit neutrophils.

On page 2085, Proost et al. find that altering a single arginine turns an inflammatory chemokine docile.

The chemokine IL-8, which activates and recruits neutrophils, is secreted as a mixture of isoforms that vary in length due to proteolysis. A cut after the first five amino end residues produces active protein, whereas cuts elsewhere inhibit activity. Proteolysis might thus be one way to control the amount of active IL-8, but it's not the only one, as Proost et al. now find. The transformation of a single arginine into the nonessential amino acid citrulline also shuts it down.

Among the IL-8 isoforms secreted by activated human immune cells, one lacked the arginine adjacent to the activating cleavage site. The lack of mutations in this isoform suggested that the alteration was post-translational, and the protein had not been trimmed, suggesting that the arginine had been replaced rather than cleaved off. The alteration did not change the isoform's mass, hinting that the replacement residue might be citrulline, which is similar in mass to arginine. Indeed, the authors found citrulline in arginine's place.

Citrulline-containing IL-8 did not efficiently activate the IL-8 receptor on neutrophils, as it resisted the activating proteolysis. It also bound poorly to sugar groups that help tether neutrophils to blood vessels. When injected into mice, this isoform thus failed to draw neutrophils to the injection site.

This modified isoform accounted for only a small fraction of the total IL-8 produced by activated cells in culture. Whether cells produce more of this isoform in vivo is not yet known. The authors have also yet to determine whether the isoform's production increases during inflammation. The enzyme that turns arginine into citrulline, peptidylarginine deiminase (PAD), is secreted mostly by monocytes, which follow neutrophils into inflamed sites. Monocytes might turn up PAD production to limit the entry of more neutrophils and prevent excessive inflammation.

PAD also citrullinated a few other chemokines, but whether these modifications are similarly inhibitory remains to be seen.