Immune system modulation of parenchymal and germinal neural progenitor cells in physiological and pathological conditions

Immune system modulation of parenchymal and germinal neural progenitor cells in physiological and pathological conditions 1. Central Nervous System as immune-specialized site The central nervous system (CNS) has long been viewed as a site in which, under physiological conditions, no immune-cell activity takes place (Engelhardt and Ransohoff, 2005). However, the perception of brain–immune interactions has dramatically changed over the past decade. It is now known that not only immune cells survey the healthy CNS but play a crucial role in the maintenance of environmental homeostasis supporting neural plasticity (Kleine and Benes, 2006; Schwartz and Kipnis, 2002). Recent studies aimed to understand how innate and adaptive immune responses contribute to the brain’s functionality, and how these activities could be modulated in the treatment of several pathologies. In this first section we will discuss how immune responses regulate and modulate the microenvironment in the CNS, and how its components (T cells targeted against brain self antigens, monocytes, resident microglial cells and derived signaling molecules) stimulate normal brain activity and interact with neural cell types. 2. Immune-based regulation on adult neurogenesis While the “immunologically privileged status” of the mammalian nervous tissue has been proposed by some as a limiting factor for CNS regeneration (Bechmann et al., 2005; Cohen and Schwartz et al., 1999), the progressive development of the adaptive immune system has also been correlated by others with the loss of CNS regenerative capacity during phylogenesis (Tanaka and Ferretti, 2009). Unlike other vertebrates, neurogenesis in mammals occurs only in two regions of the mature brain: the subependymal zone of the lateral wall of the lateral ventricle (SEZ) and the subgranular layer of the dentate gyrus of the hippocampus (SGZ) (Garcia-Verdugo et al., 1998; Kempermann et al., 2004). It has been recently discovered that immune cells participate in the maintenance of these stem niches in the adult brain (Butovsky et al., 2005; Eraldht et al., 2003; Ziv et al., 2006). Under normal homeostatic conditions, neurogenesis is supported by the interaction of resident microglia and CNS-specific T-cells, whose activity is constitutively regulated by adaptive immunity. Deficiency in adaptive immunity (e.g. in immune deficient SCID mouse; Ziv et al., 2006) is associated with reduced neurogenesis and impaired learning and memory. At difference with this ‘neurogenesis-supportive’ role of immune cells, conditions of uncontrolled local immune activity (i.e. inflammation) impair neurogenesis. Inflammation associated microglia are known to produce pro-inflammatory cytokines which are associated with reduced neurogenesis in the hippocampus. Moreover, several data support the idea that immunosuppression favors the mobilization of endogenous neural stem cells and positively regulate tissue regeneration after injury (Monje et al., 2003; Ekdahl et al., 2003; Erlandsson et al., 2010; Saino et al., 2010). In this section we will scrutinize recent studies focusing on complexity of neuroimmune relationship. In particular, we will discuss how adaptive immunity could influence neurogenesis through the production of several factors, including cytokines (pro/anti-inflammatory), chemokines and growth factors (i.e. IGF-1, BDNF and GDNF). Here, we will examine the context ? cosa si intende? dependent microglia phenotypes (cytokine-activated microglia vs LPS-activated microglia and chronically-activated microglia) and their beneficial or detrimental effects on neurogenesis. 3. Immune system regulation of parenchymal neural progenitors In the adult brain no constitutive neurogenesis takes place outside the typical neurogenic niches. However, the mature parenchyma retains two kind of glial progenitors, namely astrocytes and NG2-positive cells, that at least in certain conditions display multipotency and neurogenic potential (Boda and Buffo, 2010). Under basal condition astrocytes play an essential homeostatic role and constitute only a small proportion amongst the actively dividing cells. However, upon injury astrocytes react leaving their quiescent state and become activated. This reactive state is characterized by distinctive morphological and biochemical features such as cell hypertrophy, upregulation of intermediate filaments, and increased cell proliferation (Pekny and Nilsson, 2005; Buffo et al., 2010). Moreover, reactive astrocytes migrate towards the injured area where they constitute the glial scar, and release factors mediating the tissue inflammatory response and remodelling after lesion. A novel view of astrogliosis derives from the finding that subsets of reactive astrocytes can recapitulate stem cell/progenitor features after damage. Most notably, reactive astroglia originates self-renewing neurospheres generating all three neural phenotypes, including neurons (Buffo et al., 2008). These findings foster the concept of astroglia as a promising target for reparative therapies (Buffo et al., 2010). Astrocytes can be direct target of immune-system derived factor during reactive gliosis. Several cytokines, including TNFα, IFNγ and IL-1 have been implicated in astrocytic activation (Buffo et al., 2010). Moreover, chemokines, such as CXCL12 and CCL5, induce in astrocytes cytokine and chemokine synthesis, proliferation and survival (Buffo et al., 2010). Additionally, gene profiling studies in astrocytes exposed to inflammatory cytokines in vitro showed profound regulations in genes involved in several cellular pathways (John et al., 2005). Beside astroglia, other glial progenitors, identified by the expression of the NG2 chrondroitin sulphate proteoglycan, reside in the adult CNS parenchyma. In basal conditions, these cells comprise the major population of cycling progenitors outside the neurogenic niches and are able to differentiate into mature oligodendrocytes (Horner et al., 2000), therefore being generally indicated as oligodendrocyte precursor cells. NG2+ cells react to a variety of pathological conditions by increasing in numbers, migrating, and possibly differentiating into a more mature phenotype (Boda and Buffo, 2010). However, lineage tracing studies indicate that, beyond generating new oligodendrocytes, reactive NG2+ progenitors can be engaged in producing a fraction of scarring astrocytes, therefore displaying a certain degree of multipotency (Boda and Buffo, 2010). Recent evidence suggests that NG2+ cell reaction is mediated by immune system-derived signaling molecules. Proliferation and differentiation of NG2+ progenitor cells can be either positively or negatively influenced by differentially activated macrophages (Schonberg et al., 2007; Wu et al., 2010). Notably, nervous tissue lesions that cause NG2+ cell reaction generally open the blood–brain barrier, indicating a direct role for peripheral immune cells/cell-derived molecules in modulating NG2+ cell response to lesion (Rhodes et al., 2006). Consistently, the bi/multipotent behavior of NG2+ cells is found affected by immune system components: generation of NG2+ cell-derived astrocytes is induced in models of immune-mediated injury (experimental autoimmune encephalomyelitis) in vivo and through exposure to the pro-inflammatory cytokines in vitro (Cassiani-Ingoni et al. 2006) In this third section we will discuss how immune system modulators (cell-cell interaction and released factors) could influence the acquisition of a stem cell-like phenotype by the glial progenitors upon injury and how the modulation of such kind of plasticity could enhance healing outcome. Finally, we will discuss how pharmacological manipulation of resident and peripheral immune system activity can be exploited to foster CNS repair and favor the integration and the survival of endogenous neural progenitors. 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