ER stress-induced IRE1α activation obliterates endotoxin tolerance through modulation of cytokine production via GSK-3βand XBP-1

Abstract Endotoxin tolerance occurs in the late phase of sepsis in order to protect cells from the early hyper-inflammatory response. However, as it induces immunosuppressive environment, septic patients in their late phase are suffering from secondary infections, particularly the bacterial pneumonia. Here we show that induction of ER stress leads to activation of GSK-3β and XBP-1 in an IRE1α-mediated manner, which in turn obliterates endotoxin tolerance. Consequently, from the lung of septic host infected with P. aeruginosa, symptoms of pneumonia have been improved and the bacteria cleared. Thus, for septic patients, determination of immune status would be helpful in guiding the selective usage of appropriate immune modulation, in that ER stress can be a novel therapeutic maneuver, restoring the immune response in patients with endotoxin tolerance.