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Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation

  • Ka, Shuk-Man1
  • Lin, Jung-Chen2
  • Lin, Tsai-Jung3
  • Liu, Feng-Cheng4
  • Chao, Louis Kuoping5
  • Ho, Chen-Lung6
  • Yeh, Li-Tzu7
  • Sytwu, Huey-Kang7
  • Hua, Kuo-Feng2, 8
  • Chen, Ann2
  • 1 National Defense Medical Center, Graduate Institute of Aerospace and Undersea Medicine, Taipei, Taiwan , Taipei (Taiwan)
  • 2 Tri-Service General Hospital, National Defense Medical Center, Department of Pathology, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC , Taipei (Taiwan)
  • 3 National Defense Medical Center, Graduate Institute of Life Sciences, Taipei, Taiwan , Taipei (Taiwan)
  • 4 Tri-Service General Hospital, National Defense Medical Center, Division of Rheumatology/Immunology and Allergy, Department of Medicine, Taipei, Taiwan , Taipei (Taiwan)
  • 5 China Medical University, Department of Cosmeceutics, Taichung, Taiwan , Taichung (Taiwan)
  • 6 Taiwan Forestry Research Institute, Division of Wood Cellulose, Taipei, Taiwan , Taipei (Taiwan)
  • 7 National Defense Medical Center, Department and Graduate Institute of Microbiology and Immunology, Taipei, Taiwan , Taipei (Taiwan)
  • 8 National Ilan University, Department of Biotechnology and Animal Science, Sec. 1, Shen-Lung Road, Ilan, Taiwan, 260, ROC , Ilan (Taiwan)
Published Article
Arthritis Research & Therapy
Springer (Biomed Central Ltd.)
Publication Date
Nov 19, 2015
DOI: 10.1186/s13075-015-0844-6
Springer Nature


IntroductionLupus nephritis (LN) is a major complication of systemic lupus erythematosus. NLRP3 inflammasome activation, reactive oxygen species (ROS) and mononuclear leukocyte infiltration in the kidney have been shown to provoke the acceleration and deterioration of LN, such as accelerated and severe LN (ASLN). Development of a novel therapeutic remedy based on these molecular events to prevent the progression of the disease is clinically warranted.MethodsCitral (3,7-dimethyl-2,6-octadienal), a major active compound in a Chinese herbal medicine Litsea cubeba, was used to test its renoprotective effects in a lipopolysaccharide (LPS)-induced mouse ASLN model by examining NLRP3 inflammasome activation, ROS and COX-2 production as well as Nrf2 activation. The analysis of mechanisms of action of Citral also involved its effects on IL-1β secretion and signaling pathways of NLRP3 inflammasome in LPS-primed peritoneal macrophages or J774A macrophages.ResultsAttenuated proteinuria, renal function impairment, and renal histopathology, the latter including intrinsic cell proliferation, cellular crescents, neutrophil influx, fibrinoid necrosis in the glomerulus, and peri-glomerular infiltration of mononuclear leukocytes as well as glomerulonephritis activity score were observed in Citral-treated ASLN mice. In addition, Citral inhibited NLRP3 inflammasome activation and levels of ROS, NAD(P)H oxidase subunit p47phox, or COX-2, and it enhanced the activation of nuclear factor E2-related factor 2 (Nrf2). In LPS-primed macrophages, Citral reduced ATP-induced IL-1β secretion and caspase-1 activation, but did not affect LPS-induced NLRP3 protein expression.ConclusionOur data show that Citral alleviates the mouse ASLN model by inhibition of the activation signal, but not the priming signal, of NLRP3 inflammasome and enhanced activation of Nrf2 antioxidant signaling.

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