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

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art_BRAGA_NLRP3_gainoffunction_in_CD4_T_lymphocytes_ameliorates_experimental_2019.PDF (2.3 MB)
Citações na Scopus
22
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
PORTLAND PRESS LTD
Autores
BRAGA, Tarcio Teodoro
BRANDAO, Wesley Nogueira
AZEVEDO, Hatylas
TERRA, Fernanda Fernandes
MELO, Amanda Campelo L.
PEREIRA, Felipe Valenca
ANDRADE-OLIVEIRA, Vinicius
HIYANE, Meire Ioshie
PERON, Jean Pierre S.
Citação
CLINICAL SCIENCE, v.133, n.17, p.1901-1916, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
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URI
https://observatorio.fm.usp.br/handle/OPI/34214
Referências
  1. Alhallaf R, 2018, CELL REP, V23, P1085, DOI 10.1016/j.celrep.2018.03.097
  2. Andalib Alireza, 2013, Adv Biomed Res, V2, P31, DOI 10.4103/2277-9175.108770
  3. Arbore G, 2016, SCIENCE, V352, DOI 10.1126/science.aad1210
  4. Balkwill F, 2004, NAT REV CANCER, V4, P540, DOI 10.1038/nrc1388
  5. Barclay W, 2017, BRAIN PATHOL, V27, P213, DOI 10.1111/bpa.12477
  6. BAUER J, 1993, J NEUROIMMUNOL, V48, P13, DOI 10.1016/0165-5728(93)90053-2
  7. Bettelli E, 1998, J IMMUNOL, V161, P3299
  8. Blanchfield JL, 2010, J LEUKOCYTE BIOL, V87, P509, DOI 10.1189/jlb.0709520
  9. Bruchard M, 2015, GENOM DATA, V5, P314, DOI 10.1016/j.gdata.2015.06.031
  10. Bruchard M, 2015, NAT IMMUNOL, V16, P859, DOI 10.1038/ni.3202
  11. Buck MD, 2017, CELL, V169, P570, DOI 10.1016/j.cell.2017.04.004
  12. Cameron AM, 2019, NAT IMMUNOL, V20, P420, DOI 10.1038/s41590-019-0336-y
  13. Carecchio M, 2011, J ALZHEIMERS DIS, V25, P179, DOI 10.3233/JAD-2011-102151
  14. Chang CH, 2013, CELL, V153, P1239, DOI 10.1016/j.cell.2013.05.016
  15. Christy AL, 2013, J AUTOIMMUN, V42, P50, DOI 10.1016/j.jaut.2012.11.003
  16. Chu CQ, 2000, J EXP MED, V192, P123, DOI 10.1084/jem.192.1.123
  17. Codarri L, 2011, NAT IMMUNOL, V12, P560, DOI 10.1038/ni.2027
  18. Cua DJ, 2003, NATURE, V421, P744, DOI 10.1038/nature01355
  19. Feriotti C, 2017, FRONT IMMUNOL, V8, DOI 10.3389/fimmu.2017.00786
  20. Gris D, 2010, J IMMUNOL, V185, P974, DOI 10.4049/jimmunol.0904145
  21. Gurung P, 2015, J CLIN INVEST, V125, P1329, DOI 10.1172/JCI79526
  22. Heppner FL, 2005, NAT MED, V11, P146, DOI 10.1038/nm1177
  23. Inoue M, 2016, NAT NEUROSCI, V19, P1599, DOI 10.1038/nn.4421
  24. Inoue M, 2013, AUTOIMMUN DIS, DOI 10.1155/2013/859145
  25. Ivanov II, 2006, CELL, V126, P1121, DOI 10.1016/j.cell.2006.07.035
  26. Jha S, 2010, J NEUROSCI, V30, P15811, DOI 10.1523/JNEUROSCI.4088-10.2010
  27. Kang ZZ, 2010, IMMUNITY, V32, P414, DOI 10.1016/j.immuni.2010.03.004
  28. Kanneganti TD, 2006, J BIOL CHEM, V281, P36560, DOI 10.1074/jbc.M607594200
  29. Lukens JR, 2014, P NATL ACAD SCI USA, V111, P1066, DOI 10.1073/pnas.1318688111
  30. Mariathasan S, 2006, NATURE, V440, P228, DOI 10.1038/nature04515
  31. Mascanfroni ID, 2013, NAT IMMUNOL, V14, P1054, DOI 10.1038/ni.2695
  32. McCandless EE, 2009, J IMMUNOL, V183, P613, DOI 10.4049/jimmunol.0802258
  33. Mehta MM, 2017, NAT REV IMMUNOL, V17, P608, DOI 10.1038/nri.2017.66
  34. Mills SY, 2007, COMPLEMENT THER MED, V15, P1, DOI 10.1002/0471142735.im1501s77
  35. Molgora M, 2018, IMMUNOL REV, V281, P233, DOI 10.1111/imr.12609
  36. Moore BB, 2006, AM J RESP CELL MOL, V35, P175, DOI 10.1165/rcmb.2005-0239OC
  37. Neumann H, 2003, CURR OPIN NEUROL, V16, P267, DOI 10.1097/01.wco.0000073926.19076.29
  38. Pare A, 2018, P NATL ACAD SCI USA, V115, pE1194, DOI 10.1073/pnas.1714948115
  39. Peng M, 2016, SCIENCE, V354, P481, DOI 10.1126/science.aaf6284
  40. Petrilli V, 2007, CELL DEATH DIFFER, V14, P1583, DOI 10.1038/sj.cdd.4402195
  41. Pierson E, 2012, IMMUNOL REV, V248, P205, DOI 10.1111/j.1600-065X.2012.01126.x
  42. Poppensieker K, 2012, P NATL ACAD SCI USA, V109, P3897, DOI 10.1073/pnas.1114153109
  43. Provoost S, 2011, J IMMUNOL, V187, P3331, DOI 10.4049/jimmunol.1004062
  44. Qiao Y, 2012, FEBS LETT, V586, P1022, DOI 10.1016/j.febslet.2012.02.045
  45. Reboldi A, 2009, NAT IMMUNOL, V10, P514, DOI 10.1038/ni.1716
  46. Renkl AC, 2005, BLOOD, V106, P946, DOI 10.1182/blood-2004-08-3228
  47. Ritter M, 2014, CLIN EXP IMMUNOL, V178, P212, DOI 10.1111/cei.12400
  48. Rostami A, 2013, J NEUROL SCI, V333, P76, DOI 10.1016/j.jns.2013.03.002
  49. Rothhammer V, 2011, J EXP MED, V208, P2465, DOI 10.1084/jem.20110434
  50. Sallusto F, 1998, IMMUNOL TODAY, V19, P568, DOI 10.1016/S0167-5699(98)01346-2
  51. Sato N, 2000, J EXP MED, V192, P205, DOI 10.1084/jem.192.2.205
  52. Shaw PJ, 2010, J IMMUNOL, V184, P4610, DOI 10.4049/jimmunol.1000217
  53. Singh I, 2018, IMMUNOBIOLOGY, V223, P549, DOI 10.1016/j.imbio.2018.06.003
  54. Siveke JT, 1998, J IMMUNOL, V160, P550
  55. Ting JPY, 2015, NAT IMMUNOL, V16, P794, DOI 10.1038/ni.3223
  56. Van den Bossche J., 2015, JOVE-J VIS EXP, V8, P1
  57. Wang LX, 2018, J IMMUNOL RES, DOI 10.1155/2018/9021037
  58. Zhang XM, 2004, INT IMMUNOL, V16, P249, DOI 10.1093/intimm/dxh029
  59. Zhou LA, 2007, NAT IMMUNOL, V8, P967, DOI 10.1038/ni1488

Coleções
Artigos e Materiais de Revistas Científicas - LIM/05
Artigos e Materiais de Revistas Científicas - ODS/03