Inflammasome activation by cell volume regulation and inflammation-associated hyponatremia: a vicious cycle

Abstract Inflammasomes are caspase-1-activating molecular platforms that produce active IL-1β and are implicated in various central nervous system (CNS) diseases. These multi-protein complexes can be activated by exposure of cells to low osmolality. The inflammasome nucleotide-binding and oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) and is hereby the main sensor of cellular osmolality. IL-1β was found to stimulate the secretion of antidiuretic hormone (ADH) from the posterior pituitary gland either by action of prostaglandin s or indirectly by causing the release of IL-6. Based on these findings, we hypothesize that the hyponatremia caused by a wide range of CNS diseases is able to induce significant cell swelling with induction of a hyposmotic intracellular environment, which activates the NLRP3 inflammasome, causing the release of IL-1β and induced by IL-1β, IL-6, which increases the production of ADH that leads to more profound hyponatremia. Supportive for this hypothesis is the finding that interleukin-1 injection can induce ADH release and hyposmotic effect of ADH induced hyponatremia can via the mechanical effect of cell swelling activate transient receptor potential channels, which via transforming growth factor b-activated kinase 1 activate NLRP3. Implications of this hypothesis if confirmed would include that hyponatremia can be exacerbated through this vicious cycle but also that the inflammasomes are key mediators of this process. Confirmation of this hypothesis would have implications for prevention and clinical management of changes in patients sodium levels related to SIADH with interventions targeting inflammatory mediator production and function of inflammasomes with the potential of prevention of permanent brain damage in a wide range of CNS diseases.