Nuclear factor κB activation impairs ependymal ciliogenesis and links neuroinflammation to hydrocephalus formation.
Hydrocephalus formation is a frequent complication of neuropathological insults associated with neuroinflammation. However, the mechanistic role of neuroinflammation in hydrocephalus development is unclear. We have investigated the function of the proinflammatory acting inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling system in neuroinflammatory processes and generated a novel mouse model that allows conditional activation of the IKK/NF-κB system in astrocytes. Remarkably, NF-κB activation in astrocytes during early postnatal life results in hydrocephalus formation and additional defects in brain development. NF-κB activation causes global neuroinflammation characterized by a strong, astrocyte-specific expression of proinflammatory NF-κB target genes as well as a massive infiltration and activation of macrophages. In this animal model, hydrocephalus formation is specifically induced during a critical time period of early postnatal development, in which IKK/NF-κB-induced neuroinflammation interferes with ependymal ciliogenesis. Our findings demonstrate for the first time that IKK/NF-κB activation is sufficient to induce hydrocephalus formation and provides a potential mechanistic explanation for the frequent association of neuroinflammation and hydrocephalus formation during brain development, namely impairment of ependymal cilia formation. Therefore, our study might open up new perspectives for the treatment of certain types of neonatal and childhood hydrocephalus associated with hemorrhages and infections.
Institute of Physiological Chemistry, Ulm University, 89081 Ulm, Germany.
Michael
M
Lattke
Alexander
A
Magnutzki
Paul
P
Walther
Thomas
T
Wirth
Bernd
B
Baumann
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D004660:Encephalitis / Q000209:etiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D018315:Glioma, Subependymal / Q000209:etiology* / Q000473:pathology; D006801:Humans; D006849:Hydrocephalus / Q000150:complications / Q000201:enzymology / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D020547:Lateral Ventricles / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008855:Microscopy, Electron, Scanning; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018709:Statistics, Nonparametric; D051996:Transcription Factor RelA / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D015815:Cell Adhesion Molecules; D018925:Chemokines; D003165:Complement System Proteins; D004318:Doxycycline; D005904:Glial Fibrillary Acidic Protein; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; C496562:Ikbkb protein, mouse