Effects of Downregulations of microglial CD11B expression in normal and neurofilament light chain knockout mice

Abstract

The pathogenesis of neurodegenerative diseases prior to the onset of symptoms is generally not clear. The present study has employed a transgenic mice with interruption of neurofilament light subunit (NFL-/-) to investigate glial reactions in the lumbar cord segments at ages from 1 to 6 months. Although protein aggregates have formed in motoneurons, no obvious motor dysfunction and microglial and astrocyte activations in the spinal cord were observed in the NFL-/- mice. Unexpectedly, a downregulation of CD11b expression in microglia was detected. Although microglia could swiftly respond to sciatic nerve injury, a delayed transformation from ramified to amoeboid microglia was observed. Differential expressions of some cytokines in the lumbar cord segments and induction of Iba-1 expression in microglia were also observed in NFL -/- mice. The drastic increases in NO generation, microglial migration and phagocytosis, significant upregulation in mRNA and protein expressions of TNF-N1, iNOS, IL-1N2 and IL-6, and remarkable activation in MAPKinase signaling pathway in normal and negative control BV-2 cells in response to LPS stimulation were significantly reduced after knockdown of the CD11b gene in BV-2 microglial cells. Besides, the conditioned medium from LPS-simulated CD11b-knockdown BV-2 cells was found to be obviously less toxic to NSC-34 neurons than that from the controls. The present study has demonstrated an inhibitory environment in the spinal cord of NFL-/- mice during early pathological development, which not only shed more lights on understanding of neuropathogenesis at earlier stage of neurodegenerative diseases and provide fundamental bases for earlier diagnosis and treatment, but also reveal that inhibition of CD11b by siRNA may reduce microglial activities and ameliorate inflammation in neurodegenerative diseases.