NLRP3 is involved in JAK2-associated neuroinflammation
TSLPR ligation activates JAK, specifically JAK1 and JAK2 but not JAK3, in primary T cells 32, 33. To further explore the role of JAK2 that mediates neuroinflammation, we applied JAK inhibitor, which is the selective and orally bioavailable JAK1/2 inhibitor widely used in myelofibrosis, to block JAK signaling. Treatment of ruxolitinib by oral administration in EAE mice resulted in significant reduction in inflammatory cells infiltration by HE staining (Fig 3A), CD4+ T cells infiltration (Fig 3B), and ultimate restoration of myelin sheath expression by Luxol Fast Blue staining (LFB) (Fig 3C) and MBP expression by western blot (Fig 3D). JAK inhibition by ruxolitinib also decreased expression of NLRP3 when compared to that without JAK inhibition in brain of EAE mice (Fig 3D). ELISA experiments show that JAK inhibition reduced IL-1β level in the brain which confirms NLRP3 hyporeactivity (Fig 3E). ELISA experiments also show reduced TSLP in the brain after JAK inhibition in EAE mice when compared to that without JAK inhibition (Fig 3F). Together, our data demonstrate that JAK2 mediates neuroinflammation via NLRP3.