title: Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5.
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.
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Alard
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Almudena
authors.initials: A
authors.lastname: Ortega-Gomez
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands.
authors.forename: Kanin
authors.initials: K
authors.lastname: Wichapong
authors.affiliation: Medizinische Klinik I, Technische Universität München, 81675 Munich, Germany.
authors.forename: Dario
authors.initials: D
authors.lastname: Bongiovanni
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Horckmans
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany. Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands.
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Leoni
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany. Department of Experimental Medicine, University of Naples, 80138 Naples, Italy.
authors.forename: Bartolo
authors.initials: B
authors.lastname: Ferraro
authors.affiliation: Department of Anesthesiology, University of Münster, 48149 Münster, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Paulin
authors.affiliation: Medizinische Klinik I, Technische Universität München, 81675 Munich, Germany.
authors.forename: Judy
authors.initials: J
authors.lastname: Ng
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Ippel
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Suylen
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany. Medizinische Klinik I, Technische Universität München, 81675 Munich, Germany. German Centre for Cardiovascular Research, partner site Munich Heart Alliance, 80336 Munich, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Blanchet
authors.affiliation: Roscoff Biological Station, Pierre et Marie Curie University, 29682 Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Gaillard
authors.affiliation: Department of Experimental Medicine, University of Naples, 80138 Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Phillipp
authors.initials: P
authors.lastname: von Hundelshausen
authors.affiliation: Department of Anesthesiology, University of Münster, 48149 Münster, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.affiliation: Walter-Brendel-Center of Experimental Medicine, Ludwig Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands.
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany. German Centre for Cardiovascular Research, partner site Munich Heart Alliance, 80336 Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.affiliation: Medizinische Klinik I, Technische Universität München, 81675 Munich, Germany. German Centre for Cardiovascular Research, partner site Munich Heart Alliance, 80336 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands.
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany. Department of Biochemistry, Cardiovascular Research Institute Maastricht, University Maastricht, 6200 Maastricht, Netherlands. German Centre for Cardiovascular Research, partner site Munich Heart Alliance, 80336 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, 80336 Munich, Germany. German Centre for Cardiovascular Research, partner site Munich Heart Alliance, 80336 Munich, Germany. Department of Pathology, Academic Medical Center, 1105 Amsterdam, Netherlands. oliver.soehnlein@gmail.com.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion; D018946:Chemokine CCL5 / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D023084:alpha-Defensins; C406413:human neutrophil peptide 1