CN pathways can drive or resolve neuroinflammatory signaling in glial cells. (A) Factors that activate glial cells, including multiple cytokine species and Aβ peptides, stimulate Ca2+ release from endoplasmic reticulum (ER) and/or Ca2+ influx across Ca2+ channels in the plasma membrane leading to CN activation. CN directly dephosphorylates and activates NFATs. CN also facilitates the recruitment of IκB kinases (IKK) to the CARMA1-Bcl10-MALT1 (CBM) complex, which, in turn, causes the phosphorylation of IκB and the release (i.e., activation) of NFΚB. NFATs and NFΚB translocate to the nucleus, and with other transcription factors, such as AP1, drive the expression of numerous cytokines involved in the generation and maintenance of neuroinflammation. (B) CN can also dephosphorylate and activate FOXO3 transcription factors, which can also synergize with NFΚB to drive immune/inflammatory signaling in glial cells. (C) Activation of IGF-1 receptors in glial cells also stimulates CN but suppresses its interaction with FOXO3. Simultaneous activation of PPARγ and NFΚB by IGF-1 regulates transcriptional programs that reduce or resolve neuroinflammation.