title: CCL5 derived from platelets increases megakaryocyte proplatelet formation.
abstract: In times of physiological stress, platelet count can transiently rise. What initiates this reactive thrombocytosis is poorly understood. Intriguingly, we found that treating megakaryocytes (MKs) with the releasate from activated platelets increased proplatelet production by 47%. Platelets store inflammatory cytokines, including the chemokine ligand 5 (CCL5, RANTES); after TRAP activation, platelets release over 25 ng/mL CCL5. We hypothesized that CCL5 could regulate platelet production by binding to its receptor, CCR5, on MKs. Maraviroc (CCR5 antagonist) or CCL5 immunodepletion diminished 95% and 70% of the effect of platelet releasate, respectively, suggesting CCL5 derived from platelets is sufficient to drive increased platelet production through MK CCR5. MKs cultured with recombinant CCL5 increased proplatelet production by 50% and had significantly higher ploidy. Pretreating the MK cultures with maraviroc prior to exposure to CCL5 reversed the augmented proplatelet formation and ploidy, suggesting that CCL5 increases MK ploidy and proplatelet formation in a CCR5-dependent manner. Interrogation of the Akt signaling pathway suggested that CCL5/CCR5 may influence proplatelet production by suppressing apoptosis. In an in vivo murine acute colitis model, platelet count significantly correlated with inflammation whereas maraviroc treatment abolished this correlation. We propose that CCL5 signaling through CCR5 may increase platelet counts during physiological stress.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA; and.
authors.forename: Kellie R
authors.identifier: http://orcid.org/0000-0002-2155-1050
authors.initials: KR
authors.lastname: Machlus
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA; and.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Johnson
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kulenthirarajan
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Forward
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
authors.forename: Mason D
authors.initials: MD
authors.lastname: Tippy
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Soussou
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
authors.forename: Saleh H
authors.initials: SH
authors.lastname: El-Husayni
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA;
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Wu
authors.affiliation: Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Boston, MA.
authors.forename: Suming
authors.initials: S
authors.lastname: Wang
authors.affiliation: Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Boston, MA.
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Watnick
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA; and Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Boston, MA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Italiano
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA; and.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Battinelli
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology; D006801:Humans; D000077592:Maraviroc; D008533:Megakaryocytes / Q000166:cytology / Q000473:pathology*; D051379:Mice; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C483024:CCL5 protein, human; C584933:CCR5 protein, human; C000592874:CCR5 protein, mouse; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc