title: Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis.
abstract: Neuroinflammation plays a key role in the occurrence and development of postoperative cognitive dysfunction (POCD). Microglia, the resident immune cells in the brain, has been increasingly recognized to contribute to neuroinflammation. Although brain mast cells (MCs) are the "first responder" in the brain injury rather than microglia, little is known about the functional aspects of MCs-microglia interactions.
  
  
  
  Male Sprague-Dawley (SD) rats were injected intracerebroventricular with MC stabilizer Cromolyn (100 μg/μl), MC stimulator C48/80 (1 μg/μl), or sterile saline 30 min before open tibial fracture surgery, and the levels of neuroinflammation and memory dysfunction were tested 1 and 3 days after surgery. In addition, the effect of activated MCs on microglia and neurons was determined in vitro.
  
  
  
  Tibial fracture surgery induced MCs degranulation, microglia activation, and inflammatory factors production, which initiated the acute brain inflammatory response and neuronal death and exhibited cognitive deficit. Site-directed preinjection of the "MCs stabilizer" disodium cromoglycate (Cromolyn) inhibited this effect, including decrease of inflammatory cytokines, reduced MCs degranulation, microglia activation, neuronal death, and improved cognitive function 24 h after the surgery. In vitro study, we found that the conditioned medium from lipopolysaccharide (LPS)-stimulated mast cells line (P815) could induce primary microglia activation through mitogen-activated protein kinase (MAPK) pathway signaling and subsequent production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, the activated P815 could directly induce neuronal apoptosis and synapse injury with microglia independently. Cromolyn could inhibit P815 activation following improved microglia activation and neuronal loss.
  
  
  
  These results implicate that activated MCs could trigger microglia activation and neuronal damage, resulting in central nervous system (CNS) inflammation, and communications of MCs with microglia and neuron could constitute a new and unique therapeutic target for CNS immune inflammation-related diseases.
authors.affiliation: Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.|Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.|Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.|Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Nana
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.|Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Susu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China. yanning_qian@aliyun.com.
authors.forename: Yanning
authors.initials: Y
authors.lastname: Qian
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D005260:Female; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D009474:Neurons / Q000276:immunology / Q000378:metabolism*; D011183:Postoperative Complications / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
keywords: Cromolyn; Mast cells; Microglia activation; Neuroinflammation; Neuronal apoptosis; Postoperative cognitive dysfunction