Tyrosine Kinase Inhibition Regulates Early Systemic Immune Changes and Modulates the Neuroimmune Response in α-Synucleinopathy.

OBJECTIVES: Neuro-inflammation is common in α-Synucleinopathies and Tauopathies; and evidence suggests a link between the tyrosine kinase Abl and neurodegeneration. Abl upregulates α-Synuclein and promotes Tau hyper-phosphorylation (p-Tau), while Abl inhibitors facilitate autophagic clearance. METHODS: A model of α-Synucleinopathy harboring human mutant A53T α-Synuclein and exhibits concomitant increase in murine p-Tau was used to determine the immunological response to Abl inhibition. RESULTS: Age-dependent alterations of brain immunity, including loss of IL-10 and decreased levels of IL-2 and IL-3 were observed in old A53T mice. Brain CCL2 and CCL5 were decreased, but CX3CL1 remained constantly elevated. Young A53T mice exhibited differential systemic and central immune profiles in parallel with increased blood markers of adaptive immunity, suggesting an early systemic immune response. Tyrosine kinase inhibitors (TKIs), including nilotinib and bosutinib reduced brain and peripheral α-Synuclein and p-Tau and modulated blood immunological responses. TKIs did not affect brain IL-10, but they changed the levels of all measured blood immune markers, except CX3CL1. TKIs altered microglia morphology and reduced the number of astrocyte and dendritic cells, suggesting beneficial regulation of microglia. CONCLUSIONS: These data indicate that tyrosine kinase inhibition affects neuro-inflammation via early changes of the peripheral immune profile, leading to modulation of the neuro-immune response to α-Synuclein and p-Tau.

A stimulation-dependent alternate core promoter links lymphotoxin α expression with TGF-ß1 and fibroblast growth factor-7 signaling in primary human T cells.

Lymphotoxin (LT)-α regulates many biologic activities, yet little is known of the regulation of its gene. In this study, the contribution to LTA transcriptional regulation of the region between the transcription and translation start sites (downstream segment) was investigated. The LTA downstream segment was found to be required for, and alone to be sufficient for, maximal transcriptional activity in both T and B lymphocytes. The latter observation suggested that an alternate core promoter might be present in the downstream segment. Characterization of LTA mRNAs isolated from primary and from transformed human T cells under different stimulation conditions identified eight unique transcript variants (TVs), including one (LTA TV8) that initiated within a polypyrimidine tract near the 3' end of the downstream segment. Further investigation determined that the LTA downstream segment alternate core promoter that produces the LTA TV8 transcript most likely consists of a stimulating protein 1 binding site and an initiator element and that factors involved in transcription initiation (stimulating protein 1, TFII-I, and RNA polymerase II) bind to this LTA region in vivo. Interestingly, the LTA downstream segment alternate core promoter was active only after specific cellular stimulation and was the major promoter used when human T cells were stimulated with TGF-ß1 and fibroblast growth factor-7. Most importantly, this study provides evidence of a direct link for crosstalk between T cells and epithelial/stromal cells that has implications for LT signaling by T cells in the cooperative regulation of various processes typically associated with TGF-ßR and fibroblast growth factor-R2 signaling.