Gasdermin D Drives the Nonexosomal Secretion of Galectin-3, an Insulin Signal Antagonist

  • J Immunol. 2019 Nov 15;203(10):2712-2723. doi: 10.4049/jimmunol.1900212.
Yihui Chen  1  2 ,  Hongbin Wang  1  2 ,  Junchen Shen  1  2 ,  Rong Deng  1  2 ,  Xiaomin Yao  1  2 ,  Qiuhong Guo  1  2 ,  Ailing Lu  1  2  3 ,  Bing Sun  1  2 ,  Yan Zhang  1  2 ,  Guangxun Meng  4  2
Affiliations
  • 1. The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100039, China; and.
  • 3. Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 4. The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China; [email protected].
PMID: 31597705 DOI: 10.4049/jimmunol.1900212
Abstract

The inflammasomes play critical roles in numerous pathological conditions largely through IL-1β and/or IL-18. However, additional effectors have been implied from multiple studies. In this study, through two independent mass spectrometry-based secretome screening approaches, we identified Galectin-3 as an effector protein of the NLRP3 inflammasome. Although the activation of AIM2 or NLRC4 inflammasome also led to Galectin-3 secretion, only the NLRP3 inflammasome controlled the serum Galectin-3 level under physiological condition. Mechanistically, active gasdermin D drove the nonexosomal secretion of Galectin-3 through the plasma membrane pores. In vivo, high-fat diet-fed NLRP3-/- mice exhibited decreased circulating Galectin-3 compared with wild-type Animals. Of note, the improved Insulin sensitivity in such NLRP3-/- mice was aggravated by infusion of recombinant Galectin-3. Moreover, Galectin-3 was essential for Insulin resistance induction in mice harboring the hyperactive NLRP3A350V allele. Thus, the inflammasome-galectin-3 axis has been demonstrated as a promising target to intervene inflammasome and/or Galectin-3 related diseases.

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