ER stress-induced inflammation: does it aid or impede disease progression

ER stress-induced inflammation: does it aid or impede disease progression

Schematic representation of IRE1a-mediated, ATF6-mediated, and PERK-mediated inflammatory transcriptional program. Following ER stress, PERK activates NF-kB via translational attenuation. The activated PERK-eIF2a arm causes translational arrest, which leads to decreased levels of IkB protein and a consequent increase in the ratio of NF-kB to IkB. This change in the ratio causes the release of NF-kB protein, which then carries out its proinflammatory transcriptional role in the nucleus. Similarly, the PERK-eIF2a arm also carries out immunomodulation via CHOP, which activates transcription of the gene for IL-23, a proinflammatory cytokine. PERK-eIF2a causes CHOP production via ATF4, whose mRNA is transcribed only under conditions of translational attenuation. Interestingly, it was recently observed that ER stress-induced CHOP activation can also negatively regulate the inflammatory responses by modulating NF-kB as well as JNK (leading to modulation of downstream AP-1 activity). By contrast, ER stress can also cause the activation of IRE1a, which can then bind the tumor-necrosis factor (TNF)-a-receptor-associated factor 2 (TRAF2). Importantly, this IRE1a–TRAF2 complex can activate IkB kinase (IKK). Activated IKK then causes IkB degradation, thereby freeing NF-kB to transcribe the proinflammatory gene program. Similarly, the IRE1a–TRAF2 complex has also been shown to activate the JNK protein, which consequently phosphorylates and activates AP-1 (which in turn transcribes its own inflammatory gene program) [99]. Finally, under conditions of ER stress, ATF6 can leave the ER and reach the Golgi complex, where it can undergo ‘regulated intramembrane proteolysis’ (RIP). During RIP, ATF6 is cleaved by local site 1 and site 2 proteases (S1P and S2P) [6,100]. The activated ATF6 fragments form homodimers and transcribe acute-phase response (APR)-associated genes, such as those encoding acute-phase proteins (APPs) [6,101].

ER stress-induced inflammation in health and disease. Crosstalk between inflammation and ER stress can either aid or impede the pathogenesis and/or progression of certain diseases. For instance, ER stress-induced inflammation and even ER stress on its own, can affect pancreatic b cells as well as adipocytes and macrophages, thereby aiding the progression of type 2 diabetes and obesity, respectively. Obesity-associated inflammation can further aid type 2 diabetes progression by suppressing insulin receptor signaling. Similarly, ER stress-induced inflammation can affect intestinal epithelial cells, Paneth cells, and goblet cells, possibly aiding the progression of inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis. Furthermore, ER stress-induced inflammation has been implicated in aiding the progression of cystic fibrosis and cigarette smoke-induced chronic obstructive pulmonary disease, both of which are chronic inflammatory airway diseases. However, the link between ER stress-induced inflammation and cancer is not as simple, although ER stress-induced inflammation has been shown to aid tumorigenesis, it has also been shown to impede tumorigenesis by inducing immunogenic cell death-based antitumor immunity.