NLRP3 gain-of-function in CD4+ T lymphocytes ameliorates experimental autoimmune encephalomyelitis

NLRP3 inflammasome (NLR Pyrin-domain-containing 3) functions as an innate sensor of several PAMPs and DAMPs (pathogen- and damage-associated molecular patterns). It has been also reported as a transcription factor related to Th2 pattern, although its role in the adaptive immunity has been controversial, mainly because the studies were performed using gene deletion approaches. In the present study we have investigated the NLRP3 gain-of-function in the context of encephalomyelitis autoimmune disease (EAE), considered to be a Th1- and Th17-mediated disease. We took advantage of an animal model with NLRP3 gain-of-function exclusively to T CD4+lymphocytes (CD4CreNLRP3fl/fl). These mice presented reduced clinical score, accompanied by less infiltrating T CD4+cells expressing both IFN-gand IL-17 at the central nervous system (CNS) during the peak of the disease. However, besides NLRP3 gain-of-function in lymphocytes, these mice lack NLRP3 expression in non-T CD4+cells. Therefore, in order to circumvent this deficiency, we transferred naïve CD4+Tcells from WT, NLRP3-/-or CD4CreNLRP3fl/flinto Rag-1-/-mice and immunized them with MOG35-55. Likewise, the animals repopulated with CD4CreNLRP3fl/flTCD4+cells presented reduced clinical score and decreased IFNgproduction at the peak of the disease. Additionally, primary effector CD4+Tcells derived from these mice presented reduced glycolytic profile, a metabolic profile compatible with Th2 cells. Finally, naïveCD4+Tcells from CD4Cr...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research