Immunological regulation of neurogenic niches in the adult brain

Abstract

In mammals, neurogenesis and oligodendrogenesis are germinal processes that occur in the adult brain throughout life. The subventricular zone (SVZ) and subgranular zone (SGZ) are the main neurogenic regions in the adult brain. Therein, resides a subpopulation of astrocytes that act as neural stem cells (NSCs). Increasing evidence indicates that pro-inflammatory and other immunological mediators are important regulators of neural precursors into the SVZ and the SGZ. There are a number of inflammatory cytokines that regulate the function of NSCs. Some of the most studied include: interleukin-1, interleukin-6, tumor necrosis factor alpha, insulin-like growth factor-1, growth-regulated oncogene-alpha, leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, interferon-gamma, monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. This plethora of immunological mediators can control the migration, proliferation, quiescence, cell-fate choices and survival of NSCs and their progeny. Thus, systemic or local inflammatory processes represent important regulators of germinal niches in the adult brain. In this review, we summarized the current evidence regarding the effects of pro-inflammatory cytokines involved in the regulation of adult NSCs under in vitro and in vivo conditions. Additionally, we described the role of proinflammatory cytokines in neurodegenerative diseases and some therapeutical approaches for the immunomodulation of neural progenitor cells.

Figure 1. The adult subventricular zone (SVZ)

A) Schematic drawing that represents the sagittal view of the adult SVZ and rostral migratory stream (RMS). B) Transmission electron microscope image of the adult SVZ showing the typical cellular composition of this neurogenic niche. C) A schematic drawing depicts the organization of SVZ neural progenitors. Type-B1 cells, the putative neural stem cells (shown in blue), generate transit amplifying progenitors or type-C cells (in green), which in turn give rise to type-A cells (shown in red). Type-B2 astrocytes (also in blue) enfold migrating neuroblast. Note that the SVZ niche is in close contact to blood vessels (BV) and the ependymal cell layer (E). V: ventricle; N: neuron

Figure 2. The adult subgranular zone (SGZ)

Schematic drawing that represents the cytoarchitecture of the SGZ. The primary progenitors (in blue), also known as type-1 cells or type-B cells, give rise to type-2 cells (in red), also known as type-D cells. Intermediate progenitors migrate locally and undergo different maturation stages (D2h, D2, D3 cells) to finally differentiate into granular neurons (N).

Figure 3. Microglia in the adult SVZ

Iba-1 immunocytochemistry to label microglial cells (inset). Note that “resting” microglia is highly branched and displays a typical ‘bushy’ morphology. By electron microscopy, a microglia cell (M) can be easily identified by its dark nucleus and cytoplasm (delineated by the arrows). Electrodense corpuses in the cytoplasm (circles) are commonly found in this type of cells. Note that microglial cytoplasmic expansions (arrows) are in close contact with type-B cells. B: Type-B cell; E: Ependymal cell; V: Ventricle.

Figure 4. Proinflammatory cytokines and NSCs in the adult brain

During neuroinflammation microglia and other immune cells produce a myriad of pro-inflammatory cytokines that activate several signaling intracellular pathways, which triggers multiple effects on the adult SGZ and SVZ progenitors.