Besides providing physical support, the perivascular space SP600125 acts as a backup immune surveillance and scavenging center by constituting a niche for several immune cells that patrol CNS vasculature, namely perivascular microglia (Bechmann et al., 2001).

The origin of perivascular microglia is not fully elucidated, but it is widely accepted now that they originate from the monocyte/macrophage lineage and are continuously and rapidly replaced by blood circulating bone marrow-derived cells (Gehrmann et al., 1995; Bechmann et al., 2001). Although perivascular microglia perform normal microglial functions, they are different due to their interaction and crosstalk with cerebral endothelial cells. For instance, they have been shown to play a major role in supporting vascular integrity and repair (Ritter et al., 2006). Perivascular space creates a special milieu that controls the behavior and fate of infiltrated immune cells. This has been unraveled by the presence of newly differentiated dendritic cells from a subset of CD14+ infiltrated monocytes when exposed to high concentrations of TGFβ and GM-CSF (Ifergan et al., 2008). Moreover, fibrinogen leakage and accumulation

in the perivascular space have been shown to induce early perivascular microglial clustering toward CNS vasculature (Davalos et al., 2012). Astrocyte endfeet ensheathe more than 90% of brain capillaries, and this interaction is crucial and essential in the function of the BBB. Astrocytes also act as scaffold cells by guiding neurons during learn more development (Jacobs and Doering, 2010) and by orienting newly formed brain capillaries (Bozoyan et al., 2012). Under physiological conditions, astrocytes communicate physically with the endothelium

through ECM proteins that act Levetiracetam as ligands for adhesion receptors, namely the integrin and dystroglycan that bridge astrocyte endfeet to endothelial cells (del Zoppo and Milner, 2006). They are characterized by their capacity to produce and secrete a wide range of bioactive molecules that control endothelial function, such as VEGF, TGFβ, bFGF, TNFα, IL-1β, IL-3, IL-6, Ang-1, B cell-activating factor (BAFF), and glial-derived neurotrophic factor (GDNF) (Igarashi et al., 1999; Chung and Benveniste, 1990; Farina et al., 2007; Abbott et al., 2006). These play a crucial role in innate immune responses. Astrocytes have been shown to express TLR2/3/4/5/9 and NOD1/2 and can produce TNFα when stimulated with LPS (Chung and Benveniste, 1990). Astrocytes act like an assistance and maintenance agent of innate immunity by supporting and orienting the beneficial effects of innate immune responses. This role of astrocytes was highlighted by using a mouse model of nonfunctional astrocytes, in which they have been shown to play a crucial role in controlling the immune responses, mediating BBB maintenance, and supporting neuronal survival and functions (Bush et al., 1999).