Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders

Abstract

Brain inflammation is a complex cellular and molecular response to stress, injury or infection of the CNS in attempt to defend against insults, clear dead and damaged neurons and return the CNS to a normal state. Inflammation in the CNS is driven by the activation of resident microglia, astrocytes and infiltrating peripheral macrophages, which release a plethora of anti- and pro-inflammatory cytokines, chemokines, neurotransmitters and reactive oxygen species. This inflammatory state inadvertently causes further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Inflammatory factors have varying effects on neural progenitor cell proliferation, migration, differentiation, survival and incorporation of newly born neurons into the CNS circuitry. The unique profile of inflammatory factors, which depends on the severity of inflammation, can have varying consequences on neurogenesis. Inflammatory factors released during mild acute inflammation usually stimulate neurogenesis; where as the factors released by uncontrolled inflammation create an environment that is detrimental to neurogenesis. This review will provide a summary of current progress in this emerging field and examine the potential mechanisms through which inflammation affects neurogenesis during neurological complications.

Figure 1. IL-1β and TNF-α reduce neural differentiation and enhance proliferation of human NPCs

Human NPCs were cultured in neural basal medium supplemented with B27 alone (A), with IL-1β (1 ng/mL) (B) or TNFα (10 ng/mL) (C). Cells were stained for Map-2 (green), GFAP (red) and Hoechst (blue). Scale bar, 200 µm. The numbers of neurons were counted in ten pictures per condition and expressed as percent neurons (D) or percent astrocytes (E) *P < 0.001 vs. control. (F, G) NPCs were treated with different concentrations of TNF-α (G) or IL-1β (F) in X-vivo media with EGF for 6 days. Cell proliferation was measured by [³H]thymidine incorporation assay. Data is presented as a percentage of control, as mean ± SD. Results represent average of three donors.

Figure 2. A proposed mechanism for the effects on neurogenesis by inflammation

During neuronal injury, neurons produce chemokines, which recruit macrophage and microglia into the brain and to the site of injury. As these macrophage and microglia enter an environment of injury or inflammation, they become activated, subsequently releasing factors that promote neurogenesis. These factors include but are not limited to neurotrophins that may act directly to enhance the survival and proliferation of NPCs, and cytokines that activate astrocytes. These activated astrocytes then produce chemokines that promote the migration of NPCs to the site of injury and release neurotrophins that promote neuronal survival. Once the NPCs receive these migratory and neurotrophic signals, the NPCs can migrate, proliferate, and differentiate into neuronal or astrocyte precursors, which then mature into neurons and astrocytes that may integrate into the CNS circuitry. However, uncontrolled inflammation with chronically activated astrocytes have both pro- and anti-neurogenic effects and release factors that are detrimental to the survival of newly born neurons.