Dysregulated or excessive inflammatory responses are the cornerstone of conditions such as sepsis. Sepsis is usually triggered by a bacterial infection and is characterised by hyperactivation of the immune system commonly referred to as a “cytokine storm”. Although pro-inflammatory cytokine production is needed to protect against pathogens and promote tissue repair, the excessive and prolonged cytokine storm characteristic of sepsis leads to multiple organ failure and death. Currently, there is no effective treatment for sepsis available.
As sepsis develops the increased level of cytokine production exceeds the capacity of the endoplasmic reticulum (ER) to synthesize and fold the cytokines properly, causing unfolded proteins to accumulate. This triggers a stress response termed the unfolded protein response (UPR) which acts to increase the capacity of the ER to deal with the unfolded protein load. IRE1, an endoplasmic reticulum (ER) localised protein is a key sensor and mediator of the UPR and has been implicated in pro-inflammatory cytokine production. IRE1, via it’s endonuclease activity activates the transcription factor XBP1s which helps drive cytokine/chemokine production. The IRE1 inhibitor, MKC-4485, inhibits the endonuclease activity of IRE1, thereby blocking its ability to produce active XBP1s. Our preliminary studies show that MKC-4485 attenuates inflammatory cytokine release and extends animal survival in a toxic shock model.
This project will use MKC-4485 to (1) demonstrate that inhibiting IRE1/XBP1s signalling in a relevant physiological animal model of bacterial sepsis will reduce immune activation, counteract excessive cytokine production and increase survival and (2) investigate whether inhibiting IRE1/XBP1s signalling in patient samples will reduce the excessive cytokine production. The specific inhibition of IRE1 activity in sepsis by MKC-4485 is a novel selective method by which to block XBP1s and attenuate cytokine production. Attenuation of cytokine production would be expected to minimize organ damage and increase survival in sepsis patients.
