ER Stress Activates the NLRP3 Inflammasome: A Novel Mechanism of Atherosclerosis

Figure 3

Ca²⁺ signal transduction events linking ER stress to NLRP3 inflammasome activation. During ER stress, calcium homeostasis in the ER is imbalanced and Ca²⁺ is released into the cytoplasm through two channel proteins, namely, RYRs and IP3R. Accumulated Ca²⁺ moves into the mitochondrial matrix via the MCU, which leads to mitochondrial calcium overload and organelle damage. Mitochondrial damage causes mtROS production, mtDNA release, and cardiolipin externalization, which activate the NLRP3 inflammasome. In addition, an increased Ca²⁺ level directly affects the process of inflammasome activation. ER: endoplasmic reticulum; NLRP3: nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3; RYRs: ryanodine receptors; IP3R: inositol 1,4,5-trisphosphate receptors; MCU: mitochondrial calcium uniporter; mtROS: mitochondrial reactive oxygen species; mtDNA: mitochondrial DNA.