NLRP3 (NALP3, cryopyrin) facilitates in vivo caspase-1, necrosis, & HMGB1 release via inflammasome-dependent and –independent pathways1

• Published in: The Journal of immunology (1950) 2009-07, Vol.183 (3), p.2008-2015
• Main Authors: Willingham, Stephen B., Allen, Irving C., Bergstralh, Daniel T., Brickey, Willie June, Huang, Max Tze-Han, Taxman, Debra J, Duncan, Joseph A., Ting, Jenny P.-Y.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900138

Bacterial infection elicits a range of beneficial as well as detrimental host inflammatory responses. Key among these responses are macrophage/monocyte necrosis, release of the pro-inflammatory factor high-mobility group box 1 protein (HMGB1), and induction of the cytokine IL-1. While the control of IL-1β has been well-studied, processes that control macrophage cell death and HMGB-1 release in animals are poorly understood. This study utilizes Klebsiella pneumonia as a model organism since it elicits all three responses in vivo . The regulation of these responses is studied in the context of the inflammasome components, NLRP3 and ASC, which are important for caspase-1 activation and IL-1β release. Using a pulmonary infection model that reflects human infection, we show that K. pneumonia -induced mouse macrophage necrosis, HMGB-1 and IL-1β release are dependent on NLRP3 and ASC. K. pneumoniae infection of mice lacking Nlrp3 results in decreased lung inflammation and reduced survival relative to control indicating the overall protective role of this gene. Macrophage/monocyte necrosis and HMGB1 release are controlled independently of caspase-1 suggesting that the former two responses are separable from inflammasome-associated functions. These results provide critical in vivo validation that the physiologic role of NLRP3 and ASC is not limited to inflammasome formation.