Proteases play multifaceted roles in regulating inflammation and metabolism via proteolytic cleavage of proteins, or by directly activating receptors. We have found certain serine proteases that upregulate transient increases in systemic blood glucose in mice. Most of these proteases share the common property of activating protease activated receptor 2 (PAR2), with PAR2-deficient mice being resistant to protease-induced hyperglycemia. Mouse hepatic tissue and primary mouse hepatocytes demonstrated that PAR2 activation directly regulates glycogenolysis in the liver to produce glucose. This process is regulated independently of insulin and stress hormones. Administration of serine proteases also resulted in PAR2-dependent upregulation of inflammatory cells and cytokines in the mouse liver. PAR2 antagonism or glycolytic inhibition with 2-deoxy-ᴅ-glucose prevents certain inflammatory mediators in the liver, suggesting that protease mediated inflammation is dependent on both glucose availability and PAR2 signalling. This talk highlights proteases and PAR2 as novel mediators of immunometabolism, driving glucose metabolism to fuel sterile inflammation via glycogenolysis, and constitutes a new link between extracellular proteases, glucose metabolism and tissue inflammation for maintenance of homeostasis.