Many different types of intercellular signaling molecules are able to trigger reactive astrogliosis or to regulate specific aspects of reactive astrogliosis, including (1) large polypeptide growth factors and cytokines such as IL6, LIF, CNTF, TNFα, INFγ, Il1, Il10, TGFβ, FGF2, etc., (2) mediators of innate immunity such as lipopolysaccharide (LPS) and other Toll-like receptor ligands, (3) neurotransmitters 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 neurodegeneration such as β-amyloid, (8) molecules associated with systemic metabolic toxicity such as NH
4
+, and (9) regulators of cell proliferation such endothelin-1, as reviewed in detail elsewhere [
226]. Such molecular mediators of reactive 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 encountered 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 functional changes in reactive astrocytes are specifically controlled by inter- and intra-cellular signaling mechanisms 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, NFκB, SOCS3, Nrf2, cAMP, Olig2 are implicated in mediating different aspects or different degrees of reactive astrogliosis 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].