Research ArticleInflammation

Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5

Science Translational Medicine  09 Dec 2015:
Vol. 7, Issue 317, pp. 317ra196
DOI: 10.1126/scitranslmed.aad5330

You are currently viewing the abstract.

View Full Text

Via your Institution

Log in through your institution

Log in through your institution


Anti-inflammatory reaches for the SKY

Inflammation aids the body’s response to infection or injury, but can cause damage if excessive or unresolved. Alard et al. now examine how two early inflammatory mediators—neutrophils and platelets—cooperate to enhance inflammation. They found that human neutrophil peptide 1 (HNP1), which is secreted from neutrophils, forms a heteromer with CCL5 on platelets, resulting in stimulated monocyte adhesion and an increase in inflammation. Disrupting this interaction with a peptide (SKY) decreased inflammation and blocked monocyte recruitment in a mouse model of myocardial infarction. If these results hold true in humans, they could form the basis for a new specific therapeutic in inflammation-associated diseases.

Abstract

In acute and chronic inflammation, neutrophils and platelets, both of which promote monocyte recruitment, are often activated simultaneously. We investigated how secretory products of neutrophils and platelets synergize to enhance the recruitment of monocytes. We found that neutrophil-borne human neutrophil peptide 1 (HNP1, α-defensin) and platelet-derived CCL5 form heteromers. These heteromers stimulate monocyte adhesion through CCR5 ligation. We further determined structural features of HNP1-CCL5 heteromers and designed a stable peptide that could disturb proinflammatory HNP1-CCL5 interactions. This peptide attenuated monocyte and macrophage recruitment in a mouse model of myocardial infarction. These results establish the in vivo relevance of heteromers formed between proteins released from neutrophils and platelets and show the potential of targeting heteromer formation to resolve acute or chronic inflammation.

View Full Text