Immune Sensors and Effectors of Health and Disease

Abstract

Since the discovery of inflammasomes more than a decade ago, there has been tremendous development in the understanding of inflammasomes as central nervous system (CNS) disease determinants. The cytokines, IL-1β and IL-18, are implicated in both acute and chronic neuroinflammatory disorders. The cells of macrophage lineage represent the powerhouse of inflammasome activation in the CNS, although other cells including astrocytes and neurons exhibit inflammasome activation in stimulus and species restricted manner. The outcomes of inflammasome activation in the CNS are wide ranging encompassing both protective and pathogenic consequences depending on the individual PAMP/DAMP, inflammasome, cell type and species. The activation of inflammasomes is a complex sequence of events that lends itself to opportunities for modulation at multiple steps and demands further exploration. However, with the current understanding of molecular mechanisms underlying the effects of inflammasome inhibitors, it is feasible to target inflammasome activation at an early stage to delay neurological disease onset and progression. A major concern remains as to whether targeting at the level of inflammasome or blocking the cytokines will be beneficial for control of neuropathogenesis. Given an early prediction of disease, targeting upstream at the level of inflammasome induction would optimize outcomes by not only limiting levels of cytokine release into the brain microenvironment, but also by reducing cell death due to pyroptosis. As new therapies are developed targeting the sensor, adaptor and effector components of inflammasomes, the prospect of regulating inflammasome activation at multiple stages may become a clinical reality, permitting improved outcomes for inflammasome-driven neurological diseases.