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

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.