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[beta]1-Integrin- and [K.sub.V]1.3 channel-dependent signaling stimulates glutamate release from Th17 cells
Ist Teil von
The Journal of clinical investigation, 2020-02, Vol.130 (2), p.715
Ort / Verlag
American Society for Clinical Investigation
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Free E-Journal (出版社公開部分のみ）
Beschreibungen/Notizen
Although the impact of Th17 cells on autoimmunity Is undisputable, their pathogenic effector mechanism Is still enigmatic. We discovered soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of [beta]1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or [K.sub.V]1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although [K.sub.V]1.3 is not expressed in CNS tissue, intrathecal administration of a [K.sub.V]1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that [beta]1-integrin-and [K.sub.V]1.3 channel-dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.