The genetics behind inflammasome regulation

The inflammasome is a cytosolic multiproteic complex that promotes proinflammatory events through the release of the cytokines IL-1β and IL-18, and in some context by the induction of a lytic cell death called pyroptosis, in response to damage, infections, or changes in the homeostasis. Due to the powerful inflammatory effect, there are several regulatory mechanisms that are essential to modulate or limit the activation of the inflammasome. When these mechanisms fail, the deregulation of the complex leads or contributes to the development of a plethora of diseases characterized by constitutive and/or chronic inflammation, such as autoinflammatory, autoimmune, cardiovascular, neurodegenerative, and metabolic diseases, cancer, or even severe complications of infectious diseases. Either environmental or genetic factors may affect the threshold and/or the level of inflammasome activation, such as hyperglycemia, hyperuricemia, auto-antibodies, unfolded proteins and fibrils, or individual genetic variants in genes coding for inflammasome receptors or effector molecules, and also in regulators. While the genetics of inflammasome itself has been elsewhere characterized and also recently reviewed by our group, less is known about how genetic variants in regulatory molecules could affect inflammatory diseases. Therefore in this work, we selected a group of known or possible regulators of the inflammasome, and through the review of genetic association studies we tried to depict the contribution of these regulators in the development of multifactorial diseases.