Figure 7.

Stages of the neuroinflammatory process in which astrocyte calcineurin may participate. Initiation, Inflammatory signals set in motion by the neuropathological process activate calcineurin, which in turn activate the canonical NFκB/NFAT pathway. Activation of local and peripheral proinflammatory mechanisms together with the recruitment of autocrine and paracrine neuroprotective mediators follows. The time course of this simultaneous anti-inflammatory and proinflammatory cascade may be critical to the eventual outcome of the inflammatory response. Both agonistic and antagonistic inflammatory signals are produced by reactive astrocytes and microglia, damaged neurons and activated endothelia, and eventually from peripheral cells recruited to the lesion site. Resolution, If already activated calcineurin is stimulated by signals such as IGF-I, a neuroprotective network is activated; Progression, if calcineurin continues to be activated by inflammatory signals, the inflammation proceeds and neurons die. Both phases may be reversibly interrelated depending on the time course of the pathological process. Mechanisms whereby calcineurin is recruited toward either inflammation or neuroprotection, which involve differential interactions with transcription factors such as PPARγ and GATA3 or proteasome degradation and which depend on the upstream signal stimulating calcineurin, warrant additional analysis.