Active EAE is induced by autoantigen immunization, whereas passive EAE is induced by the adoptive transfer of encephalitogenic T cells. Although the NLRP3 inflammasome is activated in both active and passive
EAE, Asc−/− and Nlrp3−/− mice can develop severe EAE if the active EAE induction regimen is aggressive. In active EAE induction, autoantigen emulsified in complete Freund’s adjuvant (CFA) plus injections of pertussis toxin is used. To induce EAE in Asc−/− and Nlrp3−/− mice, increased dosages of heat-killed Mycobacterium tuberculosis (Mtb) in CFA alone are sufficient. A similar observation was reported in a study using Casp1−/− mice, selleck chemicals llc in which disease susceptibility is associated with repeated immunization, and high dosages or high MHC-binding affinity of antigen peptides. These studies suggest the presence of an NLRP3 inflammasome-independent pathway in progression of EAE. In addition, the studies cited herein suggest that dosages of adjuvant and/or the abundance of high-affinity antigen shift EAE to an NLRP3
inflammasome-independent disease. Two earlier reports on NLRP3 inflammasome in EAE showed important but contrasting results. Aloxistatin clinical trial One showed susceptibility of Nlrp3−/− mice to EAE, while the other showed resistance of Nlrp3−/− mice. As a result, the requirement of NLRP3 inflammasome in EAE was considered to be controversial, wherein the “basis for these conflicting data” was said to be unknown. Here, we assume that the two distinct results reflect two different subtypes of EAE: NLRP3 inflammasome-dependent and -independent. The EAE induced in Asc−/− and Nlrp3−/− mice are clearly NLRP3 inflammasome-independent. Astemizole However, in wild-type mice, two subtypes of EAE, NLRP3 inflammasome-dependent
and -independent, may be occasionally occurring at the same time, particularly when disease induction is not aggressive enough. In other words, the two subtypes are not mutually exclusive during EAE development. Depending on the triggers of the disease, and the genetic environment at hand, it is possible that the balance between the two subtypes may be altered. We have therefore shown that aggressive immunization induces NLRP3 inflammasome-independent EAE. We must then ask: What is the equivalent to such NLRP3 inflammasome-independent EAE in human disease? If there is NLRP3 inflammasome-independent MS, it might be caused by intensive stimulation on innate immune cells, or by other factors that provide strong autoantigen affinity to T cells. This, we believe, is an important and intriguing possibility. Although IFN-β is a first-line drug to treat MS, it has been found that one-third of patients do not respond to IFN-β treatment. Is IFN-β still effective without activated NLRP3 inflammasome, which is a target of IFN-β? This question was addressed in NLRP3 inflammasome-independent EAE. Results suggest that IFN-β was not effective in treating EAE in Asc−/− and Nlrp3−/− mice.