Modulation of neutrophil function through emperipolesis

通过伸入调节中性粒细胞功能

• 批准号: 10091401
• 负责人: Peter A Nigrovic
• 金额: $ 17.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091401
• 关键词: 3-Dimensional; Adoptive Transfer; Arthritis; Arthritogenic; Biological Models; Biological Process; Blood; Blood Circulation; Blood Platelets; Bone Marrow; Cell Communication; Cells; Cytoplasm; Data; Disease; Emperipolesis; Enzymes; Experimental Arthritis; Exposure to; Flow Cytometry; Funding; Genus Hippocampus; Hand; Health; Histologic; Hybrids; Image; Immunology; In Vitro; Inflammatory; Inflammatory Arthritis; Interleukin-1; Investigation; Joints; K/BxN model; Label; Laboratories; Libraries; Marrow; Mediating; Mediator of activation protein; Megakaryocytes; Membrane; Metabolism; Methods; Microscopy; Modeling; Mus; Natural Immunity; Paper; Participant; Pathogenicity; Pathway interactions; Pharmacology; Phenotype; Population; Positioning Attribute; Process; Production; Reactive Oxygen Species; Rest; Role; Route; Serum; Soldier; Source; Stress; Surface; System; Testing; Three-Dimensional Imaging; Time; Ursidae Family; Work; base; cytokine; exome; exosome; experimental study; foot; frontier; high reward; high risk; in vitro Model; in vivo; inhibitor/antagonist; innovation; intravital microscopy; migration; mouse model; neutrophil; novel; peripheral blood; tool; two-photon

Project Summary For almost 50 years it has been known that neutrophils regularly appear within megakaryocytes (MKs), a histological phenomenon termed emperipolesis. Using new tools we developed to study this process in vitro and in vivo, we found that emperipolesis is common and increases with experimental inflammatory stress in a murine system. Neutrophils penetrate into the MK cytoplasm, donating a fraction of their surface membrane to platelets before emerging viable and intact. Our preliminary data show that neutrophils take up MK-derived exosomes during emperipolesis and emerge with enhanced migratory capacity. Building on these results, we explore the hypothesis that emperipolesis is a novel cell-in-cell interaction that modulates the function of neutrophils. We test this hypothesis in two independent but complementary aims. In Aim I, we examine the effect of emperipolesis, and in particular of MK exosomes, on neutrophil effector functions, metabolism, and in vivo migration in neutrophil-dependent K/BxN serum transfer arthritis. In Aim II, we employ whole-mount 3D marrow imaging, 2-photon in vivo microscopy, and specific MK deletion and potentially emperipolesis blockade to test the possibility that emperipolesis represents a quantitatively important pathway of neutrophil egress from bone marrow in vivo, including in experimental arthritis. Together, these studies will define a new form of cooperation between MKs and neutrophils that modulates the ability of neutrophils to participate in health and disease. More generally, building upon our recent identification of MKs as a source of IL-1 in arthritis, these studies continue to develop the understanding of MKs and neutrophils as participants in systemic inflammatory disease. These “high risk, high reward” studies of a previously overlooked biological process, widely conserved across mammalian species, will set the stage for an extended investigation of emperipolesis as a novel cell-in-cell phenomenon.

项目总结