2. Academic Validation
  3. Src-family kinase-Cbl axis negatively regulates NLRP3 inflammasome activation

Src-family kinase-Cbl axis negatively regulates NLRP3 inflammasome activation

  • Cell Death Dis. 2018 Oct 31;9(11):1109. doi: 10.1038/s41419-018-1163-z.
I-Che Chung 1,  Sheng-Ning Yuan 1,  Chun-Nan OuYang 1,  Hsin-Chung Lin 2 3,  Kuo-Yang Huang 4,  Yu-Jen Chen 5 6,  An-Ko Chung 7,  Ching-Liang Chu 8,  David M Ojcius 9 10 11,  Yu-Sun Chang 1 7 12,  Lih-Chyang Chen 13
Affiliations

Affiliations

  • 1 Molecular Medicine Research Center, Chang Gung University, Taoyuan, 333, Taiwan.
  • 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan.
  • 3 Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, Taipei, 114, Taiwan.
  • 4 Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, 114, Taiwan.
  • 5 Department of Medical Research, Mackay Memorial Hospital, New Taipei City, 251, Taiwan.
  • 6 Department of Radiation Oncology, Mackay Memorial Hospital, New Taipei City, 251, Taiwan.
  • 7 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
  • 8 Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
  • 9 Department of Biomedical Sciences, University of the Pacific Arthur A. Dugoni School of Dentistry, San Francisco, CA, 94103, USA.
  • 10 Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, 333, Taiwan.
  • 11 Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou, 333, Taiwan.
  • 12 Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou, 333, Taiwan.
  • 13 Department of Medicine, Mackay Medical College, New Taipei City, 252, Taiwan. [email protected].
PMID: 30382081 DOI: 10.1038/s41419-018-1163-z
Abstract

Activation of the NLRP3 inflammasome is crucial for immune defense, but improper and excessive activation causes inflammatory diseases. We previously reported that Pyk2 is essential for NLRP3 inflammasome activation. Here we show that the Src-family kinases (SFKs)-Cbl axis plays a pivotal role in suppressing NLRP3 inflammasome activation in response to stimulation by nigericin or ATP, as assessed using gene knockout and gene knockdown cells, dominant active/negative mutants, and pharmacological inhibition. We reveal that the phosphorylation of Cbl is regulated by SFKs, and that phosphorylation of Cbl at Tyr371 suppresses NLRP3 inflammasome activation. Mechanistically, Cbl decreases the level of phosphorylated Pyk2 (p-Pyk2) through ubiquitination-mediated proteasomal degradation and reduces mitochondrial ROS (mtROS) production by contributing to the maintenance of mitochondrial size. The lower levels of p-Pyk2 and mtROS dampen NLRP3 inflammasome activation. In vivo, inhibition of Cbl with an analgesic drug, hydrocotarnine, increases inflammasome-mediated IL-18 secretion in the colon, and protects mice from dextran sulphate sodium-induced colitis. Together, our novel findings provide new insights into the role of the SFK-Cbl axis in suppressing NLRP3 inflammasome activation and identify a novel clinical utility of hydrocortanine for disease treatment.

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