16 low and there are few proliferating or newly generated astrocytes and it appears that the majority of astrocytes are post-mitotic and long-lived [33, 45, 97, 167]. Experimental analysis of cell proliferation indicates that GFAP up reg- ulation and hypertrophy can occur in mild or moderate astrogliosis in the absence of proliferation and increase in cell number [226]. The appearance of newly proliferated astrocytes occurs in severe diffuse reactive astrogliosis and severe reactive astrogliosis with compact glial scar for- mation as discussed above (Figs. 3c, 4c, d). In human specimens, actively dividing reactive astrocytes have been particularly reported in association with infection and acute demyelinating lesions [45]. The source of newly divided scar-forming astrocytes is not well established, and may include mature astrocytes that re-enter the cell cycle as well as progenitor cells in the local parenchyma or in the periventricular regions [30, 33, 37, 77, 133, 141, 226]. Molecular triggers and regulators of reactive astrogliosis and glial scar formation Many different types of intercellular signaling molecules are able to trigger reactive astrogliosis or to regulate spe- ciﬁc aspects of reactive astrogliosis, including (1) large polypeptide growth factors and cytokines such as IL6, LIF, CNTF, TNFa, INFc, Il1, Il10, TGFb, FGF2, etc., (2) mediators of innate immunity such as lipopolysaccharide (LPS) and other Toll-like receptor ligands, (3) neuro- transmitters such as glutamate and noradrenalin, (4) purines such as ATP, (5) reactive oxygen species (ROS) including nitric oxide (NO), (6) hypoxia and glucose deprivation, (7) products associated with neurodegenera- tion such as b-amyloid, (8) molecules associated with systemic metabolic toxicity such as NH4?, and (9) regu- lators of cell proliferation such endothelin-1, as reviewed in detail elsewhere [226]. Such molecular mediators of reac- tive astrogliosis can be released by all cell types in CNS tissue, including neurons, microglia, oligodendrocyte lineage cells, pericytes, endothelia, and other astrocytes, in response to all forms of CNS insults, ranging from subtle cellular perturbations that release some of the speciﬁc factors just listed, to cell stretching as might be encoun- tered during acceleration/deceleration CNS injury and which releases ATP, to intense tissue injury and cell death that release various intracellular molecules that signal intense tissue damage (Fig. 2b) [226]. It is also becoming clear that different molecular, morphological, and func- tional changes in reactive astrocytes are speciﬁcally controlled by inter- and intra-cellular signaling mecha- nisms that reﬂect the speciﬁc contexts of the stimuli and produce speciﬁc and gradated responses of reactive astrogliosis [226]. For example, the different intracellular signaling pathways associated with STAT3, NFjB, 123 Acta Neuropathol (2010) 119:7–35 SOCS3, Nrf2, cAMP, Olig2 are implicated in mediating different aspects or different degrees of reactive astrogli- osis such as GFAP up regulation, cell hypertrophy, proliferation, and pro- or anti-inﬂammatory effects [226]. Molecular triggers that lead to proliferation of reactive astrocytes in vivo are incompletely characterized but include EGF, FGF, endothelin 1, and ATP [77, 121, 161]. Functions of reactive astrogliosis and glial scar formation Concepts about reactive astrogliosis have long been dom- inated by the recognition over 100 years ago that scars formed by reactive astrocytes inhibit axon regeneration and by the interpretation that this scar formation was the main impediment to functional recovery after CNS injury or disease [192]. The ensuing over 100-year-long emphasis on glial scar formation as an inhibitor of axon regeneration has often led to a generalized negative view of reactive astrogliosis per se, and there has been a tendency among certain authors to typecast the entire process of reactive astrogliosis as a uniformly negative and maladaptive phenomenon that unavoidably causes neurotoxicity, inﬂammation, or chronic pain. This stereotyped viewpoint has sometimes led to the simplistic notion that total inhibition of reactive astrogliosis can be regarded as a therapeutic strategy. This absolutely negative viewpoint of reactive astrogliosis is no longer tenable and it is now clear from many different lines of experimental evidence that there is a normal process of reactive astrogliosis that exerts essential beneﬁcial functions and does not do harm. As reviewed in detail elsewhere [226], many studies using transgenic and experimental animal models provide com- pelling evidence that reactive astrocytes protect CNS cells and tissue by (1) uptake of potentially excitotoxic gluta- mate [33, 198, 234], (2) protection from oxidative stress via glutathione production [42, 216, 234, 245], (3) neuropro- tection via adenosine release [125], (4) protection from NH4? toxicity [193], (5) neuroprotection by degradation of amyloid-beta peptides [113], (6) facilitating blood brain barrier repair [33], (7) reducing vasogenic edema after trauma, stroke or obstructive hydrocephalus [33, 264], (8) stabilizing extracellular ﬂuid and ion balance and reducing seizure threshold [264], and (9) limiting the spread of inﬂammatory cells or infectious agents from areas of damage or disease into healthy CNS parenchyma [33, 59, 68, 95, 123, 156, 175, 251]. Reactive astrogliosis, glial scar formation and CNS inﬂammation Of particular interest as regards functions of reactive astrocytes, is recent evidence that reactive astrogliosis and