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

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 Nlrp3^A350V allele. Thus, the inflammasome-galectin-3 axis has been demonstrated as a promising target to intervene inflammasome and/or Galectin-3 related diseases.