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Brain tissue-derived autoimmune encephalitis cytokine TSLP primes neuroinflammation by activating JAK2-NLRP3 axis
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  • Xueyuan Yu,
  • Jiajia Lv,
  • Jun Wu,
  • Yong Chen,
  • Fei Chen,
  • Li Wang
Xueyuan Yu
Nanjing Brain Hospital
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Jiajia Lv
Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital
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Jun Wu
Nanjing Brain Hospital
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Yong Chen
Nanjing Brain Hospital
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Fei Chen
Nanjing Brain Hospital
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Li Wang
Nanjing Brain Hospital
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Abstract

Hyperactivation of NLRP3 inflammasome contributes to the neuroinflammation in autoimmune disorders, but the underlying regulating mechanism remains to be elucidated. We here demonstrate that mice lacking thymic stromal lymphopoietin receptor gene (Tslpr-/-) exhibit significant decreases in experimental autoimmune encephalitis (EAE) score, reduced CD4+ T cells infiltration, and restored expression of myelin basic protein (MBP) in the brain after induction of EAE by injection of myelin oligodendrocyte glycoprotein35-55 (MOG35-55) . TSLPR signals through Janus Kinase 2 (JAK2) to activate NLRP3. Tslpr-/- mice of EAE show decreased phosphorylation of JAK2 and expression of NLRP3 in the brain. In wild type (WT) mice after induction of EAE, inhibition of JAK2 by ruxolitinib inflammatory and CD4+ cell infiltration, decreased expression of NLRP3, and restored BMP expression in the brain. Ruxolitinib also decreased levels of IL-1β and TSLP in brain of EAE mouse when compared to that without ruxolitinib treatment. Further results with NLRP3 inhibitor MCC950 in EAE mouse of WT verified the proinflammatory role of NLRP3 by showing decreased inflammatory cells and CD4+ T cells, restored MBP expression, and declined levels of IL-1β and TSLP in the brain. In patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis we found increased level of NLRP3 and IL-1β in CSF when compared to that in control subjects. These findings highlight TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders.
16 Aug 2021Submitted to Clinical & Experimental Immunology
17 Aug 2021Assigned to Editor
17 Aug 2021Submission Checks Completed
17 Aug 2021Reviewer(s) Assigned