HSP70 is a negative regulator of NLRP3 inflammasome activation

• Published in: Cell death & disease 2019-03, Vol.10 (4), p.256-256, Article 256
• Main Authors: Martine, Pierre, Chevriaux, Angélique, Derangère, Valentin, Apetoh, Lionel, Garrido, Carmen, Ghiringhelli, François, Rébé, Cédric
• Format: Article
• Language: English
• Subjects: 13/21; 14/34; 631/250/127/1213; 631/250/256/2177; 64/60; 82/80; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biochemistry; Biomedical and Life Sciences; Bone marrow; CARD Signaling Adaptor Proteins - metabolism; Caspase; Caspase 1 - metabolism; Caspase-1; Cell activation; Cell Biology; Cell Culture; Disease Models, Animal; Female; Heat shock proteins; Heat-Shock Response; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Hyperthermia; IL-1β; Immunology; Inflammasomes; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Inflammatory diseases; Interleukin-1beta - metabolism; Leucine; Life Sciences; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - cytology; Macrophages - enzymology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Peritonitis; Peritonitis - genetics; Peritonitis - metabolism; Proteins; Pyrin protein; Rodents; THP-1 Cells
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1491-7

The NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome is a multi-protein complex, aimed at producing IL-1β in response to danger signals which must be tightly regulated. Here we investigated the importance of the stress sensor, Heat Shock Protein 70 (HSP70) on NLRP3 inflammasome activation. HSP70 deficiency leads to the worsening of NLRP3-dependent peritonitis in mice. HSP70 deficiency also enhances caspase-1 activation and IL-1β production in murine Bone Marrow-Derived Macrophages (BMDMs) under NLRP3 activator treatment in vitro. This observation is associated with an increased number and size of Apoptosis associated Speck-like protein containing a CARD domain (ASC)/NLRP3 specks. Conversely, the overexpression of HSP70 in BMDMs decreases caspase-1 activation and IL-1β production under NLRP3 activator treatment. HSP70 interacts with NLRP3 and this interaction is lost upon NLRP3 inflammasome activation. Heat shock inhibits NLRP3 inflammasome activation in vitro and inhibits peritonitis in mice. Therefore this study provides evidence on the inhibitory role of HSP70 on NLRP3 inflammasome and open the possibility of treating inflammatory diseases via HSP70 induction and/or by hyperthermia.