title: Inflammasome activation by cell volume regulation and inflammation-associated hyponatremia: A vicious cycle.
abstract: Inflammasomes are caspase-1-activating molecular platforms that produce active interleukin (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) 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 prostaglandins 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 evidence for this hypothesis is the finding that IL-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 β-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 syndrome of inappropriate antidiuretic hormone secretion (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.
authors.affiliation: Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton LU4ODZ, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Eisenhut
authors.affiliation: Department of Microbiology, BK 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Yu
authors.affiliation: Department of Pediatric Nephrology, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea. Electronic address: shinji@yuhs.ac.
authors.forename: J I
authors.initials: JI
authors.lastname: Shin
mesh_terms: D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism; D006801:Humans; D007010:Hyponatremia / Q000378:metabolism / Q000503:physiopathology*; D007177:Inappropriate ADH Syndrome / Q000378:metabolism / Q000503:physiopathology; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D009994:Osmolar Concentration; D009995:Osmosis; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein