The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis

Abstract

NLRP3 inflammasome hyperactivation contributes to neuroinflammation in autoimmune disorders, but the underlying regulatory mechanism remains to be elucidated. We demonstrate that compared with wild-type (WT) mice, mice lacking thymic stromal lymphopoietin (TSLP) receptor (TSLPR) (Tslpr -/- mice) exhibit a significantly decreased experimental autoimmune encephalitis (EAE) score, reduced CD4 + T cell infiltration, and restored myelin basic protein (MBP) expression in the brain after EAE induction by myelin oligodendrocyte glycoprotein35-55 (MOG35-55). TSLPR signals through Janus kinase (JAK)2, but not JAK1 or JAK3, to induce NLRP3 expression, and Tslpr -/- mice with EAE show decreased JAK2 phosphorylation and NLRP3 expression in the brain. JAK2 inhibition by ruxolitinib mimicked loss of TSLPR function in vivo and further decreased TSLP expression in the EAE mouse brain. The NLRP3 inhibitor MCC950 decreased CD4 + T cell infiltration, restored MBP expression, and decreased IL-1β and TSLP levels, verifying the proinflammatory role of NLRP3. In vitro experiments using BV-2murine microglia revealed that TSLP directly induced NLRP3 expression, phosphorylation of JAK2 but not JAK1orJAK3, and IL-1β release, which were markedly inhibited by ruxolitinib. Furthermore, EAE induction led to an increase in the Th17 cell number, a decrease in the regulatory T (Treg) cell number in the blood, and an increase in the expression of the cytokine IL-17A in the WT mouse brain, which was drastically reversed in Tslpr -/- mice. In addition, ruxolitinib suppressed the increase in IL-17A expression in the EAE mouse brain. These findings identify TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders.

Targeting the Epithelium-Derived Innate Cytokines: From Bench to Bedside

“…Moreover, these mice display impaired differentiation of T cells into myelin oligodendrocyte glycoprotein-specific effector and memory T cells ( 123 ). Yu et al ( 124 ) showed that TSLP receptor-deficient ( Tslpr − / − ) mice also exhibit resistance to EAE. Moreover, they found that TSLPR signaling induces neuroinflammation by activating Janus kinase, which then hyperactivates the NLR family pyrin domain containing 3 inflammasome ( 124 ), which in turn drives systemic T H 1 and T H 17 inflammation and chemotaxis of immune cells to the CNS.…”

“…Yu et al ( 124 ) showed that TSLP receptor-deficient ( Tslpr − / − ) mice also exhibit resistance to EAE. Moreover, they found that TSLPR signaling induces neuroinflammation by activating Janus kinase, which then hyperactivates the NLR family pyrin domain containing 3 inflammasome ( 124 ), which in turn drives systemic T H 1 and T H 17 inflammation and chemotaxis of immune cells to the CNS. Thus, blocking TSLP signaling may be a prospective target for MS.…”

Focus on the Role of the NLRP3 Inflammasome in Multiple Sclerosis: Pathogenesis, Diagnosis, and Therapeutics

“…In EAE, the expression levels of NLRP3 mRNA and protein were increased (Gris et al, 2010 ; Ke et al, 2017 ), and compared to the wild-type mice, Nlrp3 −/− mice showed reduced numbers of Th1 and Th17 cells in the spinal cord and peripheral lymphoid tissues and markedly mild EAE (Gris et al, 2010 ; Inoue et al, 2012a ). Recently, it was reported that thymic stromal lymphopoietin (TSLP) could directly induce NLRP3 expression through phosphorylation of Janus kinase (JAK) 2, and Tslpr −/− mice showed decreased NLRP3 expression and EAE scores (Yu et al, 2021 ). Zhang et al ( 2018 ) reported that a deficiency of microglial ASC could attenuate the expansion of T cells and the infiltration of neutrophil, which suggests the important role of ASC in EAE.…”

Computational Identification of Ligand-Receptor Pairs that Drive Human Astrocyte Development

“…Interestingly, TGFβ2 and BMP4 can act both synergistically and antagonistically in various settings and tissues 63 . DKK1 is a negative regulator of Wnt signaling 64 , while TSLP is a pleiotropic cytokine that has been traditionally implicated in T-cell maturation and proinflammatory immune responses 65 . Finally, NLGN1 is a postsynaptic cell adhesion molecule important for neuronal spinogenesis, synaptic formation, and even astrocyte morphogenesis 66 .…”