Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis

Maugeri, Norma; Capobianco, Annalisa; Rovere‐Querini, Patrizia; Ramirez, Giuseppe A.; Tombetti, Enrico; Valle, Patrizia Della; Monno, Antonella; D’Alberti, Valentina; Gasparri, Anna Maria; Franchini, Stefano; D’Angelo, Armando; Bianchi, Marco E.; Manfredi, Angelo A.

doi:10.1126/scitranslmed.aao3089

Cited by 138 publications

(160 citation statements)

References 71 publications

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“…Microparticles were derived from platelets and expressed the damage-associated molecular pattern HMGB1. An inhibitor of HMGB1 attenuated neutrophil activation [131] Natural killer A peculiar natural killer cell phenotype in SSc patients was identified characterized by decreased chemokine and activation receptors expression. These SSc-derived natural killer cells were potent inducers of endothelial microparticle release suggesting that there may be a role for natural killer cells in the activation of endothelial cells in SSc [133] Innate lymphoid Type 2 innate lymphoid (ILC2) cells are elevated in patients with SSc.…”

Section: Resultsmentioning

confidence: 99%

The immunopathogenesis of fibrosis in systemic sclerosis

Brown

O’Reilly

2018

Clinical and Experimental Immunology

148

113

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Summary Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterized by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. How these different cell types interact to contribute to SSc is complicated, and can involve cell‐to‐cell interactions and communication via cytokines, including transforming growth factor (TGF)‐β, interleukin (IL)‐6 and IL‐4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis.

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Section: Resultsmentioning

confidence: 99%

The immunopathogenesis of fibrosis in systemic sclerosis

Brown

O’Reilly

2018

Clinical and Experimental Immunology

148

113

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“…The mechanisms behind the movement of cytoplasmic HMGB1 out of the cell, however, are much less well understood, and may be cell, tissue, and stimulus dependent. Active secretion of HMGB1 has been shown to occur via exocytosis of HMGB1‐containing secretory lysosomes, microparticles, and exosomes . However, the details of the signaling pathways leading to HMGB1 exocytosis, including targeting to specific vesicles, remain elusive.…”

Section: Getting Hmgb1 Out Of Cells and Into The Circulationmentioning

confidence: 99%

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Deng

Scott

Fan

et al. 2019

Journal of Leukocyte Biology

131

101

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High mobility group box 1 (HMGB1) is a multifunctional nuclear protein, probably known best as a prototypical alarmin or damage-associated molecular pattern (DAMP) molecule when released from cells. However, HMGB1 has multiple functions that depend on its location in the nucleus, in the cytosol, or extracellularly after either active release from cells, or passive release upon lytic cell death. Movement of HMGB1 between cellular compartments is a dynamic process induced by a variety of cell stresses and disease processes, including sepsis, trauma, and hemorrhagic shock.Location of HMGB1 is intricately linked with its function and is regulated by a series of posttranslational modifications. HMGB1 function is also regulated by the redox status of critical cysteine residues within the protein, and is cell-type dependent. This review highlights some of the mechanisms that contribute to location and functions of HMGB1, and focuses on some recent insights on important intracellular effects of HMGB1 during sepsis and trauma. K E Y W O R D S AIM2, autophagy, caspase-11, DAMPs, pyroptosis 2 NUCLEAR-TO-CYTOPLASM SHUTTLING OF HMGB1 HMGB1 consists of 215 aa residues, and contains 2 HMG DNAbinding domains, designated as A and B boxes, together with a negatively charged C-terminal acidic region. 14 Two nuclear localization sites (NLSs), one located in the A box (aa 28-44) and one in the B box (aa 179-185), control the nuclear localization of HMGB1 under homeostatic states. 14 Posttranslational modifications of NLS sites, including acetylation, phosphorylation, and methylation, regulate the ability of HMGB1 to translocate to the cytoplasm during cellular stress.Once in the cytoplasm HMGB1 can affect multiple inflammatory responses, and can be actively released into the extracellular space and circulation.

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“…For example, HMGB1 has been shown to cause vascular barrier dysfunction and accumulation of neutrophils (Nawaz & Mohammad, ). Based on a recent publication showing that platelet‐derived MPs from patients with systemic sclerosis express high levels of HMGB1 (Maugeri et al, ), we asked, in our experiments, whether neutrophil‐derived MPs also contain HMGB1. By using transmission immunoelectron microscopy, we found that neutrophil‐derived MPs attached to NETs express HMGB1.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular trap‐microparticle complexes trigger neutrophil recruitment via high‐mobility group protein 1 (HMGB1)‐toll‐like receptors(TLR2)/TLR4 signalling

Wang

Hawez

et al. 2019

British J Pharmacology

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Background and Purpose Recent data suggest that neutrophil extracellular traps (NETs) form aggregates with microparticles (MPs) upon activation of neutrophils although the functional role of NET‐MP complexes remain elusive. The objective of this study was to examine the role of NET‐MP aggregates in leukocyte recruitment in vivo. Experimental Approach PMA stimulation of murine bone marrow neutrophils generated NET‐MP complexes and pretreatment with caspase and calpain inhibitors resulted in the formation of NETs depleted of MPs. Leukocyte–endothelium interactions were studied by using intravital microscopy of the mouse cremaster microcirculation. Key Results Intrascrotal injection of NET‐MP aggregates dose‐dependently increased leukocyte recruitment. In contrast, leukocyte responses were markedly reduced after administration of NETs depleted of MPs. Neutrophil depletion abolished intravascular and extravascular leukocytes in response to challenge with NET‐MP complexes. Electron microscopy revealed that NET‐associated MPs express HMGB1. Notably, immunoneutralization of HMGB1 markedly decreased NET‐MP complex‐induced neutrophil accumulation. Moreover, inhibition of TLR2 and TLR4 significantly reduced neutrophil recruitment in response to NET‐MP aggregates. Conclusions and Implications These data show that NET‐MP complexes are potent inducers of neutrophil recruitment, which is dependent on HMGB1 expressed on MPs and mediated via TLR2 and TLR4. Blocking MP binding to NETs or downstream inhibition of the HMGB1‐TLR2/TLR4 axis might provide useful targets to attenuating NET‐dependent tissue damage in acute inflammation.

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Platelet microparticles sustain autophagy-associated activation of neutrophils in systemic sclerosis

Cited by 138 publications

References 71 publications

The immunopathogenesis of fibrosis in systemic sclerosis

The immunopathogenesis of fibrosis in systemic sclerosis

Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Neutrophil extracellular trap‐microparticle complexes trigger neutrophil recruitment via high‐mobility group protein 1 (HMGB1)‐toll‐like receptors(TLR2)/TLR4 signalling

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