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Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease.

ABSTRACT: Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.

SUBMITTER: Petzold T

PROVIDER: S-EPMC9767676 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease.

Petzold Tobias T Zhang Zhe Z Ballesteros Iván I Saleh Inas I Polzin Amin A Thienel Manuela M Liu Lulu L Ul Ain Qurrat Q Ehreiser Vincent V Weber Christian C Kilani Badr B Mertsch Pontus P Götschke Jeremias J Cremer Sophie S Fu Wenwen W Lorenz Michael M Ishikawa-Ankerhold Hellen H Raatz Elisabeth E El-Nemr Shaza S Görlach Agnes A Marhuenda Esther E Stark Konstantin K Pircher Joachim J Stegner David D Gieger Christian C Schmidt-Supprian Marc M Gaertner Florian F Almendros Isaac I Kelm Malte M Schulz Christian C Hidalgo Andrés A Massberg Steffen S

Immunity 20221021 12

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependen ...[more]

PMID: 36272416

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Project description:AbstractCytoskeletal remodeling and mitochondrial bioenergetics play important roles in thrombocytopoiesis and platelet function. Recently, α-actinin-1 mutations have been reported in patients with congenital macrothrombocytopenia. However, the role and underlying mechanism of α-actinin-1 in thrombocytopoiesis and platelet function remain elusive. Using megakaryocyte (MK)-specific α-actinin-1 knockout (KO; PF4-Actn1-/-) mice, we demonstrated that PF4-Actn1-/- mice exhibited reduced platelet counts. The decreased platelet number in PF4-Actn1-/- mice was due to defects in thrombocytopoiesis. Hematoxylin and eosin staining and flow cytometry revealed a decrease in the number of MKs in the bone marrow of PF4-Actn1-/- mice. The absence of α-actinin-1 increased the proportion of 2 N-4 N MKs and decreased the proportion of 8 N-32 N MKs. Colony-forming unit-MK colony formation, the ratio of proplatelet formation-bearing MKs, and MK migration in response to stromal cell-derived factor-1 signaling were inhibited in PF4-Actn1-/- mice. Platelet spreading, clot retraction, aggregation, integrin αIIbβ3 activation, and CD62P exposure in response to various agonists were decreased in PF4-Actn1-/- platelets. Notably, PF4-Actn1-/- platelets inhibited calcium mobilization, reactive oxygen species (ROS) generation, and actin polymerization in response to collagen and thrombin. Furthermore, the PF4-Actn1-/- mice exhibited impaired hemostasis and thrombosis. Mechanistically, proteomic analysis of low-ploidy (2-4 N) and high-ploidy (≥8 N) PF4-Actn1-/- MKs revealed that α-actinin-1 deletion reduced platelet activation and mitochondrial function. PF4-Actn1-/- platelets and Actn1 KO 293T cells exhibited reduced mitochondrial membrane potential, mitochondrial ROS generation, mitochondrial calcium mobilization, and mitochondrial bioenergetics. Overall, in this study, we report that mice with α-actinin-1 deficiency in MKs exhibit low platelet count and impaired platelet function, thrombosis, and mitochondrial bioenergetics.

Project description:IntroductionCrohn's disease (CD) is characterized by chronic inflammation and intestinal fibrosis leading to lifelong complications. However, the disease pathogenesis remains elusive, and the therapeutic options are limited. Here, we investigated the interaction between neutrophils and intestinal fibroblasts in the development of CD immunofibrosis, a disease mechanism predisposing to inflammatory and fibrotic complications.MethodsPeripheral neutrophils, enriched neutrophil extracellular traps (eNETs), serum, primary intestinal fibroblasts (PIFs) and intestinal biopsies from CD, ulcerative colitis (UC) patients, and healthy individuals (HI), were studied. Transcriptome analysis of neutrophils, multi-cytokine profiling and cell-based functional assays at mRNA/protein level were performed.ResultsCompared to UC, PIFs from CD patients, independently to the presence of strictures, displayed a distinct pro-fibrotic phenotype characterized by negative Krüppellike Factor-2 (KLF2) and increased cellular communication network factor-2 (CCN2) expression leading to collagen production. In both UC and CD, PIFs-derived IL-8 acted as a culprit chemoattractant for neutrophils in the intestine, where CD neutrophils were accumulated close to fibrotic lesions. Functionally, only CD neutrophils via eNETs induced a CD-like phenotype in HI PIFs, suggesting their fibrotic plasticity. High IFNa in serum and IFΝ-responsive signature in peripheral neutrophils were observed in CD, distinguishing it from UC. Moreover, CD serum stimulated the release of fibrogenic eNETs from neutrophils in an IFNa-dependent manner, suggesting the priming role of IFNa in circulating neutrophils. Inhibition of eNETs or JAK signaling in neutrophils or PIFs prevented the neutrophil-mediated fibrotic effect on PIFs. Furthermore, both serum IFNa levels and mRNA levels of key IFN signaling components in neutrophils were wellcorrelated with CD severity.ConclusionsThis study reveals the important role of the IFNa/neutrophil/fibroblast axis in CD immunofibrosis, suggesting candidate biomarkers and putative therapeutic targets.

Dataset Information

Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease.

Publications

Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease.

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