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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Braga, Tarcio Teodoro [1, 2] ; Brandao, Wesley Nogueira [3] ; Azevedo, Hatylas [4] ; Terra, Fernanda Fernandes [2] ; Melo, Amanda Campelo L. [2] ; Pereira, Felipe Valenca [2] ; Andrade-Oliveira, Vinicius [2, 5] ; Hiyane, Meire Ioshie [2] ; Peron, Jean Pierre S. [3] ; Saraiva Camara, Niels Olsen [6, 2, 7]
Total Authors: 10
[1] Univ Fed Parana, Dept Pathol, Curitiba, Parana - Brazil
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Transplantat Immunol Lab, Sao Paulo - Brazil
[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Neuroimmune Interact Lab, Sao Paulo - Brazil
[4] Univ Fed Sao Paulo, Div Urol, Dept Surg, Sao Paulo - Brazil
[5] Fed Univ ABC, Ctr Nat & Human Sci, Bernardos Lab, Sao Paulo - Brazil
[6] Univ Fed Sao Paulo, Nephrol Div, Sao Paulo - Brazil
[7] Univ Sao Paulo, Fac Med, Renal Physiopathol Lab, Sao Paulo - Brazil
Total Affiliations: 7
Document type: Journal article
Source: Clinical Science; v. 133, n. 17, p. 1901-1916, SEP 13 2019.
Web of Science Citations: 0

NLRP3 inflammasome {[}NLR (nucleotide-binding domain, leucine-rich repeat containing protein) 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 Th 17-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-gamma and 1L-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 naive CD4- T cells from WT, NLRP3-/- or CD4CreNLRP3fl/fl into Rag-1-/- mice and immunized them with MOG(35-55). Likewise, the animals repopulated with CD4CreNLRP3fl/fl T CD4+ cells presented reduced clinical score and decreased IFN-gamma production at the peak of the disease. Additionally, primary effector CD4(+) T cells derived from these mice presented reduced glycolytic profile, a metabolic profile compatible with Th2 cells. Finally, naive CD4(+) T cells from CD4CreNLRP3fl/fl mice under a Th2-related cytokine milieu cocktail exhibited in vitro an increased IL-4 and IL-13 production. Conversely, naive CD4(+) T cells from CD4CreNLRP3fl/fl mice under Th1 differentiation produced less IFN-gamma and T-bet. Altogether, our data evidence that the NLRP3 gain-of-function promotes a Th2-related response, a pathway that could be better explored in the treatment of multiple sclerosis. (AU)

FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
Grantee:Niels Olsen Saraiva Câmara
Support type: Research Projects - Thematic Grants
FAPESP's process: 17/22504-1 - TAM receptors and their ligands Gas6 and Pros1 on the ZIKV Congenital Syndrome in Experimental Models
Grantee:Jean Pierre Schatzmann Peron
Support type: Regular Research Grants
FAPESP's process: 14/06992-8 - Cellular, molecular and immunological mechanisms generated through NLRP activation
Grantee:Tárcio Teodoro Braga
Support type: Scholarships in Brazil - Post-Doctorate