Caspases and their role in inflammation and ischemic neuronal death. Focus on caspase-12

Caspases are cysteine proteases, which play important roles in different processes including, apoptosis and inflammation. Caspase-12, expressed in mouse and human, is classified as an inflammatory caspase. However, in humans caspase-12 gene has acquired different mutations that result in the expression of different variants. Caspase-12 is generally recognized as a negative regulator of the inflammatory response induced by infections, because it inhibits the activation of caspase-1 in inflammasome complexes, the production of the pro-inflammatory cytokines IL-1β and IL-18 and the overall response to sepsis. In contrast, caspase-4, the human paralog of caspase-12, exerts a positive modulatory action of the inflammatory response to infectious agents. The role of caspase-12 and caspase-4 in inflammation associated with cerebral ischemia, a condition that results from a transient or permanent reduction of cerebral blood flow, is still unknown. Among the mechanisms involved in ischemic brain injury, apoptosis and inflammation have important roles. Under these conditions, disturbances in the homeostasis of the endoplasmic reticulum (ER) take place, leading to ER stress, caspase activation and apoptosis. Caspase-12 up-regulation and processing has been observed after the ischemic episode but its role in apoptosis is controversial. Cleavage of caspase-4 also occurs during ER stress but its role in ischemic brain injury is unknown. Throughout this review evidence supporting a role of caspase-12 and caspase-4 on the modulation of the inflammatory response to infection and their potential contribution to ER stress-induced apoptosis, is discussed. Understanding the actions of rodent caspase-12 and human caspase-4 will help us to elucidate their role in different pathological conditions, which to date is not well understood.