The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines including IL-1β and IL-18. We show that NLRP3 inflammasome activation is restricted to interphase of the cell cycle by NEK7, a serine/threonine kinase previously implicated in mitosis. NLRP3 inflammasome activation requires NEK7, which binds to the NLRP3 leucine-rich repeat domain in a kinase-independent manner downstream from the induction of mitochondrial ROS. This interaction is necessary for NLRP3-ASC complex formation, ASC oligomerization, and caspase-1 activation. NEK7 promotes the NLRP3-dependent cellular inflammatory response to intraperitoneal monosodium urate challenge, and the development of experimental autoimmune encephalitis in mice. Our findings suggest NEK7 serves as a cellular switch that enforces mutual exclusivity between the inflammasome response and cell division.
These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system.
Background: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an ␣4 1 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection. Objective: To test the effect of natalizumab treatment on the CD4 ϩ /CD8 ϩ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.
Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.
This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.
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