The role of IRE1α in the regulation of cytokine production

Abstract

Inositol-requiring enzyme 1 (IRE1), a key mediator of the unfolded protein response (UPR), has emerging roles within innate immunity and cancer progression. Here we examine how IRE1 signalling influences the production of cytokines and chemokines in health and disease. Specifically, we ask how IRE1 dependent signalling (i) contributes to cytokine and chemokine production in monocytic cells following tolllike receptor (TLR) stimulation and (ii) the influence of IRE1 dependent signalling on cytokine/chemokine production in pancreatic ductal adenocarcinoma (PDAC). The NLRP3 inflammasome is a central control point within innate immunity. Assembly of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome facilitates caspase-1 activation inducing the processing of the key cytokine pro-IL1β, which is required to mount an effective innate immune response. Following stimulation of TLR4 we observed selective activation of IRE1 RNase signalling in monocytic cells which when inhibited reduced NLRP3 inflammasome assembly and levels of bioactive IL-1β. By carefully dissecting the various steps required for formation of the NLRP3 inflammasome we found that IRE1 RNase activity specifically aided structural assembly of the inflammasome. This work highlights a new and important role for IRE1 within innate immunity and suggests that IRE1 activity contributes to the maintenance of cellular health. In addition to examining the influence of IRE1 in cellular health, we have also investigated how IRE1 dependent signalling can contribute to disease progression and in particular its role in pancreatic cancer. PDAC is a tumour type known to exhibit a highly inflammatory phenotype with conditions that stimulate basal ER stress levels. We demonstrate that inhibition of IRE1 RNase activity reduces cytokine release and proliferation in PDAC cells. Pancreatic Stellate Cells (PSC) are a key component of the PDAC tumour microenvironment (TME). These cells encapsulate the PDAC tumour and through the production of secreted factors help to create an environment conducive for PDAC growth. We observed that ablating IRE1 RNase activity increased production of secreted factors associated with enhanced natural killer cell activation and decreased factors linked with PDAC tumorigenesis. These findings suggest a multifaceted role for IRE1 controlled cytokine networks in PDAC progression.