Oxidative stress elicits platelet/leukocyte inflammatory interactions via HMGB1: a candidate for microvessel injury in sytemic sclerosis.
OBJECTIVE
An abnormal generation of reactive oxygen species (ROS) is thought to contribute to systemic sclerosis (SSc), fostering autoimmunity, fibrosis, and vascular inflammation. The function of the prototypic damage-associated molecular pattern, high mobility group box 1 (HMGB1), depends on its redox status. Here we investigate whether oxidative stress regulates the cross-talk between leukocytes and platelets via HMGB1, thus contributing to vessel inflammation in SSc.


RESULTS
The oxidation of HMGB1 amplified its ability to activate neutrophils, as detected assessing the redistribution of primary granule molecules and the transactivation of the β2 integrin chain CD18. Activated platelets are a source of bioactive HMGB1 and via P-selectin stimulated neutrophils to generate ROS. Oxidized extracellular HMGB1, soluble or associated to platelet membrane or to platelet-derived microparticles (PDμPs), further increased leukocyte activation. Leukocyte activation abated in the presence of inhibitors of HMGB1 or of catalase, which catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen. The redistribution of the content of primary granules and the transactivation of β2 integrins characterized blood leukocytes of SSc patients and membrane HMGB1 was significantly higher in patients with pulmonary hypertension or with diffuse SSc. HMGB1(+) microparticles (μPs) purified from SSc patients, but not HMGB1(-) μPs purified from control subjects, activated in vitro healthy neutrophils, and HMGB1 inhibitors reversed the effects of μPs.


CONCLUSIONS
ROS dramatically increase the ability of extracellular HMGB1 to activate blood leukocytes. This event might contribute to maintain the microvascular injury of patients with SSc.
1 Division of Regenerative Medicine, Stem Cells and Gene Therapy, and Department of Medicine, San Raffaele Scientific Institute , Milano, Italy .
Norma
N
Maugeri
Patrizia
P
Rovere-Querini
Mattia
M
Baldini
Elena
E
Baldissera
Maria Grazia
MG
Sabbadini
Marco E
ME
Bianchi
Angelo A
AA
Manfredi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D018821:CD18 Antigens / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D007962:Leukocytes / Q000378:metabolism* / Q000502:physiology; D008297:Male; D055806:Microvessels / Q000378:metabolism* / Q000503:physiopathology; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000503:physiopathology; D015533:Transcriptional Activation / Q000502:physiology
D018821:CD18 Antigens; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D019007:P-Selectin; D017382:Reactive Oxygen Species