Platelet HMGB1 is required for efficient bacterial clearance in intra-abdominal bacterial sepsis in mice.

Thrombocytopenia impairs host defense and hemostasis in sepsis. However, the mechanisms of how platelets regulate host defense are not fully understood. High-mobility group box 1 (HMGB1), a danger-associated molecular pattern protein, is released during infection and contributes to the pathogenesis of sepsis. Platelets express HMGB1, which is released on activation and has been shown to play a critical role in thrombosis, monocyte recruitment, and neutrophil extracellular trap (NET) production. However, the contribution of platelet HMGB1 to host defense is unknown. To determine the role of platelet HMGB1 in polymicrobial sepsis, platelet-specific HMGB1 knockout (HMGB1 platelet factor 4 [PF4]) mice were generated and were subjected to cecal ligation and puncture (CLP), a clinically relevant intra-abdominal sepsis model. Compared with HMGB1 Flox mice and wild-type (WT) mice, HMGB1 PF4 mice showed significantly higher bacterial loads in the peritoneum and blood, an exaggerated systemic inflammation response, and significantly greater mortality after CLP. Deletion of HMGB1 in platelets was associated with lower platelet-derived chemokines (PF4 and RANTES) in the peritoneal cavity, and a decrease of platelet-neutrophil interaction in the lung after CLP. In vitro, neutrophils cocultured with activated HMGB1 knockout platelets showed fewer platelet-neutrophil aggregates, reduced reactive oxygen species (ROS) burst as compared with control. Taken together, these data reveal an unrecognized role of platelet HMGB1 in the regulation of neutrophil recruitment and activation via modulation of platelet activation during sepsis.

[1]  A. Tsung,et al.  Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA , 2018, Scientific Reports.

[2]  P. Kubes,et al.  Platelets and infection. , 2016, Seminars in immunology.

[3]  A. Walch,et al.  Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. , 2016, Blood.

[4]  A. Zwinderman,et al.  Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. , 2016, Blood.

[5]  A. Kettle,et al.  Reactive Oxygen Species and Neutrophil Function. , 2016, Annual review of biochemistry.

[6]  Christopher W Seymour,et al.  Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[7]  H. Thorlacius,et al.  Platelet‐Derived CCL5 Regulates CXC Chemokine Formation and Neutrophil Recruitment in Acute Experimental Colitis , 2016, Journal of cellular physiology.

[8]  M. E. Shaker,et al.  Therapeutic Opportunities in Damage-Associated Molecular Pattern-Driven Metabolic Diseases. , 2015, Antioxidants & redox signaling.

[9]  Simon C Watkins,et al.  Platelet-derived HMGB1 is a critical mediator of thrombosis. , 2015, The Journal of clinical investigation.

[10]  A. Zarbock,et al.  Platelets in leucocyte recruitment and function. , 2015, Cardiovascular research.

[11]  T. Billiar,et al.  Damage‐associated molecular pattern–activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury , 2015, Hepatology.

[12]  Ronit Vogt Sionov,et al.  Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. , 2015, Cell reports.

[13]  T. van der Poll,et al.  Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. , 2014, Blood.

[14]  J. Ware,et al.  Platelets: balancing the septic triad. , 2014, Blood.

[15]  Michael R. Yeaman,et al.  Platelets: at the nexus of antimicrobial defence , 2014, Nature Reviews Microbiology.

[16]  M. Bianchi,et al.  Oxidative stress elicits platelet/leukocyte inflammatory interactions via HMGB1: a candidate for microvessel injury in sytemic sclerosis. , 2014, Antioxidants & redox signaling.

[17]  T. Taniguchi,et al.  Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection , 2013, Proceedings of the National Academy of Sciences.

[18]  Simon C Watkins,et al.  Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis , 2013, The Journal of Immunology.

[19]  T. Standiford,et al.  The function of neutrophils in sepsis , 2012, Current opinion in infectious diseases.

[20]  P. Rani,et al.  The Role of Platelet Factor 4 in Local and Remote Tissue Damage in a Mouse Model of Mesenteric Ischemia/Reperfusion Injury , 2012, PloS one.

[21]  L. Varani,et al.  HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4 , 2012, The Journal of experimental medicine.

[22]  T. Ueno,et al.  HMGB-1 as a useful prognostic biomarker in sepsis-induced organ failure in patients undergoing PMX-DHP. , 2011, The Journal of surgical research.

[23]  K. Tracey,et al.  HMGB1 is a therapeutic target for sterile inflammation and infection. , 2011, Annual review of immunology.

[24]  R. Flaumenhaft,et al.  Platelet alpha-granules: basic biology and clinical correlates. , 2009, Blood reviews.

[25]  J. Michel,et al.  Mediators of neutrophil recruitment in human abdominal aortic aneurysms , 2009, Cardiovascular research.

[26]  P. Płonka,et al.  Platelets augment respiratory burst in neutrophils activated by selected species of gram-positive or gram-negative bacteria. , 2008, Folia histochemica et cytobiologica.

[27]  P. Devos,et al.  Impact of thrombocytopenia on outcome of patients admitted to ICU for severe community-acquired pneumonia. , 2007, The Journal of infection.

[28]  K. Tracey,et al.  Hemorrhagic Shock Induces NAD(P)H Oxidase Activation in Neutrophils: Role of HMGB1-TLR4 Signaling1 , 2007, The Journal of Immunology.

[29]  Stephen R. Clark,et al.  Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood , 2007, Nature Medicine.

[30]  Kevin J. Tracey,et al.  High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal , 2005, Nature Reviews Immunology.

[31]  R. Califf,et al.  Antibodies to Platelet Factor 4/Heparin are Associated with Elevated Endothelial Cell Activation Markers in Patients with Acute Coronary Ischemic Syndromes , 2004, Journal of Thrombosis and Thrombolysis.

[32]  Shi-hong Lu,et al.  Platelet factor 4 enhances the adhesion of normal and leukemic hematopoietic stem/progenitor cells to endothelial cells. , 2004, Leukemia research.

[33]  H. Rauvala,et al.  Occurrence of Amphoterin (HMG1) as an Endogenous Protein of Human Platelets that Is Exported to the Cell Surface upon Platelet Activation , 2000, Thrombosis and Haemostasis.

[34]  K. Tracey,et al.  HMG-1 as a late mediator of endotoxin lethality in mice. , 1999, Science.