UPR signaling pathways can be specifically activated in the absence of ER stress, for example, by growth factor signaling or infections: IRE1 can be activated by internalized Vascular Endothelial Growth Factor (VEGF) receptor 2 through direct interaction [74], while Toll-like receptors (TLRs) in macrophages activate it by a NADPH oxidase-dependent signal [75]. The gene discussed is ERN1; the disease is infection.