title: IL-1β induces hypomyelination in the periventricular white matter through inhibition of oligodendrocyte progenitor cell maturation via FYN/MEK/ERK signaling pathway in septic neonatal rats.
abstract: Neuroinflammation elicited by microglia plays a key role in periventricular white matter (PWM) damage (PWMD) induced by infectious exposure. This study aimed to determine if microglia-derived interleukin-1β (IL-1β) would induce hypomyelination through suppression of maturation of oligodendrocyte progenitor cells (OPCs) in the developing PWM. Sprague-Dawley rats (1-day old) were injected with lipopolysaccharide (LPS) (1 mg/kg) intraperitoneally, following which upregulated expression of IL-1β and IL-1 receptor 1 (IL-1R1 ) was observed. This was coupled with enhanced apoptosis and suppressed proliferation of OPCs in the PWM. The number of PDGFR-α and NG2-positive OPCs was significantly decreased in the PWM at 24 h and 3 days after injection of LPS, whereas it was increased at 14 days and 28 days. The protein expression of Olig1, Olig2, and Nkx2.2 was significantly reduced, and mRNA expression of Tcf4 and Axin2 was upregulated in the developing PWM after LPS injection. The expression of myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3"-phosphodiesterase (CNPase) was downregulated in the PWM at 14 days and 28 days after LPS injection; this was linked to reduction of the proportion of myelinated axons and thinner myelin sheath as revealed by electron microscopy. Primary cultured OPCs treated with IL-1β showed the failure of maturation and proliferation. Furthermore, FYN/MEK/ERK signaling pathway was involved in suppression of maturation of primary OPCs induced by IL-1β administration. Our results suggest that following LPS injection, microglia are activated and produce IL-1β in the PWM in the neonatal rats. Excess IL-1β inhibits the maturation of OPCs via suppression of FYN/MEK/ERK phosphorylation thereby leading to axonal hypomyelination.
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.|Shantou University Medical College (FCS), Shantou, Guangdong, People's Republic of China. 515063.
authors.forename: Fengcai
authors.initials: F
authors.lastname: Shen
authors.affiliation: Department of Neonatology, Guangdong General Hospital, Guangzhou, 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, People's Republic of China.|Shantou University Medical College (FCS), Shantou, Guangdong, People's Republic of China. 515063.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
authors.forename: Qianpeng
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
authors.forename: Hongke
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Critical Care and Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000090322:Homeobox Protein Nkx-2.2; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000502:physiology; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D058953:Neural Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D055495:Neurogenesis / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000648:ultrastructure; D017207:Rats, Sprague-Dawley; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism* / Q000473:pathology; D066127:White Matter / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000090322:Homeobox Protein Nkx-2.2; C000594089:IL1B protein, rat; C580803:IL1R1 protein, rat; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C000715628:Nkx2-2 protein, rat; D053573:Receptors, Interleukin-1 Type I
keywords: FYN/MEK/ERK signaling pathway; IL-1β; PWMD; microglia; sepsis