NFATc3 promotes Ca²⁺‐dependent MMP3 expression in astroglial cells

Abstract

Increase in intracellular calcium ([Ca(2+) ]i ) is a key mediator of astrocyte signaling, important for activation of the calcineurin (CN)/nuclear factor of activated T cells (NFAT) pathway, a central mediator of inflammatory events. We analyzed the expression of matrix metalloproteinase 3 (Mmp3) in response to increases in [Ca(2+) ]i and the role of the CN/NFAT pathway in this regulation. Astrocyte Mmp3 expression was induced by overexpression of a constitutively active form of NFATc3, whereas other MMPs and tissue inhibitor of metalloproteinases (TIMP) were unaffected. Mmp3 mRNA and protein expression was also induced by calcium ionophore (Io) and 2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (Bz-ATP) and Mmp3 upregulation was prevented by the CN inhibitor cyclosporin A (CsA). Ca(2+) -dependent astrocyte Mmp3 expression was also inhibited by actinomycin D, and a Mmp3 promoter luciferase reporter was efficiently activated by increased [Ca(2+) ]i , indicating regulation at the transcriptional level. Furthermore, Ca(2+) /CN/NFAT dependent Mmp3 expression was confirmed in pure astrocyte cultures derived from neural stem cells (Ast-NSC), demonstrating that the induced Mmp3 expression occurs in astrocytes, and not microglial cells. In an in vivo stab-wound model of brain injury, MMP3 expression was detected in NFATc3-positive scar-forming astrocytes. Because [Ca(2+) ]i increase is an early event in most brain injuries, these data support an important role for Ca(2+) /CN/NFAT-induced astrocyte MMP3 expression in the early neuroinflammatory response. Understanding the molecular pathways involved in this regulation could provide novel therapeutic targets and approaches to promoting recovery of the injured brain.

Nuclear factor of activated T cells in cancer development and treatment

“…Foldynova-Trantirkova et al reported that CK1ε mutants activate the Wnt/Rac1/JNK and NFAT pathways, resulting in decreased breast cancer cell adhesion and increased migration [77]. Matrix metalloproteinases (MMPs) are well-known basement membrane proteolytic enzymes that are activated during tumor invasion [78], and they are induced by NFATs in myocytes, glomerular mesangial cells and astrocytes [79][80][81]. One recent study has found that NFAT1 is overexpressed in glioblastoma multiforme cells, and its overexpression increases the invasive potential of tumor cells through MMP-7 and MMP-9 upregulation [82].…”

Calcineurin and glial signaling: neuroinflammation and beyond

“…, NFATs 2 and 4) have also been detected in astrocytes and microglia at the mRNA and protein levels [47,56,59,66-68,72-74]. Several recent studies have reported a striking increase in NFAT4 expression in a subgroup of astrocytes following acute CNS trauma [67,68,73], though the subcellular localization of NFAT4 seemed to be limited to the cytosol, with very little expression found in astrocyte nuclei [67]. Other groups have shown that NFAT4 is indeed active in astrocytes and regulates the expression of transcripts involved in Aβ production [66], as discussed in a later section of this review.…”

Erythropoietin: Powerful protection of ischemic and post-ischemic brain

“…Calcium 25 and RONS 26,27 induce astrocytes, 25,26,28 microglia 25 and cerebrovascular endothelium 29–31 to secrete matrix metalloproteinases (MMPs), a class of enzymes that degrade protein components of the extracellular matrix and of the tight junctions within the capillary endothelium that comprise the blood-brain barrier (BBB). 32–35 By oxidizing cysteine residues in the autoinhibitory domain of proMMPs, RONS activate MMPs by the ‘cysteine switch’ mechanism.…”