title: Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats.
abstract: Axon development plays a pivotal role in the formation of synapse, nodes of Ranvier, and myelin sheath. Interleukin-1β (IL-1β) produced by microglia may cause myelination disturbances through suppression of oligodendrocyte progenitor cell maturation in the septic neonatal rats. Here, we explored if a microglia-derived IL-1β would disturb axon development in the corpus callosum (CC) following lipopolysaccharide (LPS) administration, and if so, whether it is associated with disorder of synapse formation in the cerebral cortex and node of Ranvier.
  
  
  
  Sprague-Dawley rats (1-day old) in the septic model group were intraperitoneally administrated with lipopolysaccharide (1 mg/kg) and then sacrificed for detection of IL-1β, interleukin-1 receptor (IL-1R1), neurofilament-68, neurofilament-160, and neurofilament-200, proteolipid, synaptophysin, and postsynaptic density 95 (PSD95) expression by western blotting and immunofluorescence. Electron microscopy was conducted to observe alterations of axonal myelin sheath and synapses in the cortex, and proteolipid expression was assessed using in situ hybridization. The effect of IL-1β on neurofilament and synaptophysin expression in primary neuron cultures was determined by western blotting and immunofluorescence. P38-MAPK signaling pathway was investigated to determine whether it was involved in the inhibition of IL-1β on neurofilament and synaptophysin expression.
  
  
  
  In 1-day old septic rats, IL-1β expression was increased in microglia coupled with upregulated expression of IL-1R1on the axons. The expression of neurofilament-68, neurofilament-160, and neurofilament-200 (NFL, NFM, NFH) and proteolipid (PLP) was markedly reduced in the CC at 7, 14, and 28 days after LPS administration. Simultaneously, cortical synapses and mature oligodendrocytes were significantly reduced. By electron microscopy, some axons showed smaller diameter and thinner myelin sheath with damaged ultrastructure of node of Ranvier compared with the control rats. In the cerebral cortex of LPS-injected rats, some axo-dendritic synapses appeared abnormal looking as manifested by the presence of swollen and clumping of synaptic vesicles near the presynaptic membrane. In primary cultured neurons incubated with IL-1β, expression of NFL, NFM, and synaptophysin was significantly downregulated. Furthermore, p38-MAPK signaling pathway was implicated in disorder of axon development and synaptic deficit caused by IL-1β treatment.
  
  
  
  The present results suggest that microglia-derived IL-1β might suppress axon development through activation of p38-MAPK signaling pathway that would contribute to formation disorder of cortical synapses and node of Ranvier following LPS exposure.
authors.affiliation: Southern Medical University, Guangzhou, 510515, People's Republic of China.|Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.|Department of Critical Care Medicine, Yueyang First People's Hospital, Yueyang, 414000, People's Republic of China.
authors.forename: Qianpeng
authors.initials: Q
authors.lastname: Han
authors.affiliation: Southern Medical University, Guangzhou, 510515, People's Republic of China.|Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.
authors.forename: Qiongyu
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.|Shantou University Medical College, Shantou, Guangdong, 515063, People's Republic of China.
authors.forename: Peixian
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.|Shantou University Medical College, Shantou, Guangdong, 515063, People's Republic of China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Anatomy, Basic medical school of Wuhan University, Wuhan, Hubei, 430071, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Anatomy, Basic medical school of Wuhan University, Wuhan, Hubei, 430071, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Neonatology, Guangzhou General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.
authors.forename: Shaoru
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China.|Shantou University Medical College, Shantou, Guangdong, 515063, People's Republic of China.
authors.forename: Fengcai
authors.initials: F
authors.lastname: Shen
authors.affiliation: Southern Medical University, Guangzhou, 510515, People's Republic of China. zenghongke@vip.163.com.|Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China. zenghongke@vip.163.com.
authors.forename: Hongke
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Southern Medical University, Guangzhou, 510515, People's Republic of China. yiyudeng666@163.com.|Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China. yiyudeng666@163.com.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D000071074:Neonatal Sepsis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D012844:Sincalide / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; D048051:p38 Mitogen-Activated Protein Kinases; D012844:Sincalide
keywords: Axon; IL-1β; LPS; Microglia; Neurofilament; PWMD; Synapse