Figure 2

Integration of stress-signalling mechanisms. Damaged or dysfunctioning cells communicate with innate immune cells by releasing intracellular factors named damage-associated molecular pattern molecules (DAMPs). During cell death, these molecules, such as calgranulines from the protein S100 A superfamily or alarmines such as the nuclear protein high-mobility group box 1 (HMGB1), are released into the extracellular space to activate the immune system. These molecules associate with pathogen-associated molecular pattern molecules (PAMPs) from destroyed pathogens to activate cellular expression of Toll-like receptors (TLRs) of the pattern recognition receptor (PRR) superfamily. Some of these receptors, specifically TLR2, 4 and 9, recognize multiple DAMPS released during stress and cell death. Proteins with abnormal conformation are processed by the proteasome S26 system in the endoplasmic reticulum, where protein kinase R-like endoplasmic reticulum kinase (PERK)-type kinases are activated; these pathways depend on Ire1 (which requires inositol) and nuclear factors, such as NF-κB and Nrf2 (NF-E2 related factor). Nrf2 controls the expression of genes encoding enzymes that remove reactive oxygen species (ROS), including heme oxygenase 1 (HO-1) and glutathione S-transferase (GST). PERK-dependent phosphorylation of Nrf2 thus coordinates a transcriptional program connecting oxidative stress and endoplasmic reticulum stress. Activation of the transcription factor CREB-H can be achieved through this endoplasmic reticulum stress; CREB-H is responsible for the acute inflammatory response in the liver with acute phase protein synthesis. Adapted from [1]. GLUT, glucose transporter; HIF, hypoxia-inducible factor; HO, heme oxygenase; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; NOS, nitric oxide synthase; PKC, protein kinase C; RAGE, receptors for advanced glycation end products; ssRNA, single-stranded RNA.