STAT3 signaling after traumatic brain injury

Abstract

Abbreviations used: A2m, a-2-macroglobulin; BBB, blood-brain barrier; Cebpb, CCAAT/enhancer-binding protein b; Cdkn1a, cyclindependent kinase inhibitor 1A; Csf2rb, colony-stimulating factor 2 receptor b; FPI, fluid-percussion brain injury; GFAP, glial fibrillary acidic protein; gp130, glycoprotein 130; GCSF, granulocyte colonystimulating factor; GSK-3b, glycogen synthase kinase-3b; Il2rc, interleukin-2 receptor c; Il4ra, interleukin-4 receptor a; Jak, Janus kinase; Mmp3, matrix metalloproteinase 3; Mpl, myeloproliferative leukemia virus oncogene; Nos2, nitric oxide synthase 2; Osm, oncostatin M; qPCR, quantitative RT-PCR; STAT3, signal transducer and activator of transcription-3; Socs3, suppressor of cytokine signaling 3; SFK, Src family kinase; TBI, traumatic brain injury. Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami MillerSchool of Medicine, Miami, Florida, USA Abstract Astrocytes respond to trauma by stimulating inflammatory signaling. In studies of cerebral ischemia and spinal cord injury, astrocytic signaling is mediated by the cytokine receptor glycoprotein 130 (gp130) and Janus kinase (Jak) which phosphorylates the transcription factor signal transducer and activator of transcription-3 (STAT3). To determine if STAT3 is activated after traumatic brain injury (TBI), adult male Sprague-Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery, and then the ipsilateral cortex and hippocampus were analyzed at various posttraumatic time periods for up to 7 days. Western blot analyses indicated that STAT3 phosphorylation significantly increased at 30 min and lasted for 24 h post-TBI. A significant increase in gp130 and Jak2 phosphorylation was also observed. Confocal microscopy revealed that STAT3 was localized primarily within astrocytic nuclei. At 6 and 24 h post-TBI, there was also an increased expression of STAT3 pathway-related genes: suppressor of cytokine signaling 3, nitric oxide synthase 2, colony stimulating factor 2 receptor b, oncostatin M, matrix metalloproteinase 3, cyclin-dependent kinase inhibitor 1A, CCAAT/enhancer-binding protein b, interleukin-2 receptor c, interleukin-4 receptor a, and a-2-macroglobulin. These results clarify some of the signaling pathways operative in astrocytes after TBI and demonstrate that the gp130-Jak2-STAT3 signaling pathway is activated after TBI in astrocytes.

Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

“…The JAK-STAT pathway includes a family of receptor-associated JAKs that can phosphorylate tyrosine residues on STATs, and activation of the JAK-STAT pathway via ischemic preconditioning could result in adaptation to ischemic stress [10]. A previous study illustrated that cytokines activate JAK2 and subsequently phosphorylate STAT3 in cerebral ischemia and other neuroinflammatory diseases [12]. The suppressor of cytokine signaling (SOCS) protein family comprises eight members that are important in the molecular regulation of cytokine signaling [13].…”

PI3K Signaling and Stat92E Converge to Modulate Glial Responsiveness to Axonal Injury

“…Indeed, activation of STAT molecules in mammalian glial cells (determined primarily by using phospho-STAT-specific antibodies) has been widely reported in response to focal brain lesion [75],[76], traumatic brain injury [77],[78], and spinal cord injury (SCI) [79]. STAT3 is a critical modulator of reactive gliosis: loss of STAT3 from astrocytes in the context of SCI has been shown to lead to attenuated activation of GFAP expression, a lack of astrocyte hypertrophy, and reduced formation of the glial scar.…”

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

“…This induction of STAT3 phosphorylation through IL-6-type signaling can result in a variety of genetic changes, including increases in GFAP expression that are associated with astrocyte activation (Hebert and O'Callaghan 2000; Oliva et al 2012; Sriram et al 2004; Zhong et al 1994). The current study is the first to show that treatment with a sigma receptor antagonist mitigates METH-induced increases in signaling through this pathway and thereby counteracts METH-induced astrogliosis.…”