Inhibition of high-mobility group box 1 protein (HMGB1) enhances bacterial clearance and protects against Pseudomonas Aeruginosa pneumonia in cystic fibrosis.
Pulmonary infection with Pseudomonas aeruginosa and neutrophilic lung inflammation significantly contribute to morbidity and mortality in cystic fibrosis (CF). High-mobility group box 1 protein (HMGB1), a ubiquitous DNA binding protein that promotes inflammatory tissue injury, is significantly elevated in CF sputum. However, its mechanistic and potential therapeutic implications in CF were previously unknown. We found that HMGB1 levels were significantly elevated in bronchoalveolar lavage fluids (BALs) of CF patients and cystic fibrosis transmembrane conductance regulator (CFTR )(-/-) mice. Neutralizing anti-HMGB1 monoclonal antibody (mAb) conferred significant protection against P. aeruginosa-induced neutrophil recruitment, lung injury and bacterial infection in both CFTR(-/-) and wild-type mice. Alveolar macrophages isolated from mice treated with anti-HMGB1 mAb had improved phagocytic activity, which was suppressed by direct exposure to HMGB1. In addition, BAL from CF patients significantly impaired macrophage phagocytotic function, and this impairment was attenuated by HMGB1-neutralizing antibodies. The HMGB1-mediated suppression of bacterial phagocytosis was attenuated in macrophages lacking toll-like receptor (TLR)-4, suggesting a critical role for TLR4 in signaling HMGB1-mediated macrophage dysfunction. These studies demonstrate that the elevated levels of HMGB1 in CF airways are critical for neutrophil recruitment and persistent presence of P. aeruginosa in the lung. Thus, HMGB1 may provide a therapeutic target for reducing bacterial infection and lung inflammation in CF.
Cardiopulmonary Toxicology, Department of Pharmaceutical Sciences, St. John's University College of Pharmacy and Allied Health Professions, Queens, New York 11439, USA.
Maria
M
Entezari
Daniel J
DJ
Weiss
Ravikumar
R
Sitapara
Laurie
L
Whittaker
Matthew J
MJ
Wargo
JianHua
J
Li
Haichao
H
Wang
Huan
H
Yang
Lokesh
L
Sharma
Binh D
BD
Phan
Mohammad
M
Javdan
Sangeeta S
SS
Chavan
Edmund J
EJ
Miller
Kevin J
KJ
Tracey
Lin L
LL
Mantell
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D024243:HMGB1 Protein / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000276:immunology*; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology*; D011550:Pseudomonas aeruginosa; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics
D000911:Antibodies, Monoclonal; D024243:HMGB1 Protein; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4