Abstract
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.
Highlights
Inflammasomes are intracellular complexes constituted by a receptor and an adaptor that enable recruitment and activation of pro-inflammatory caspases such as caspase[1] and the maturation of pro-inflammatory cytokines such as IL-1β or IL-181
Wild type (WT) or Hsp70−/− mice were intraperitoneally injected with aluminum salts (Alum) or monosodium urate (MSU)
We show here that Heat Shock Protein 70 (HSP70) is essential in the regulation of NLRP3 inflammasome activation
Summary
Inflammasomes are intracellular complexes constituted by a receptor and an adaptor that enable recruitment and activation of pro-inflammatory caspases such as caspase[1] and the maturation of pro-inflammatory cytokines such as IL-1β or IL-181. Differentiated cells were primed with LPS (100 ng/mL—Sigma-Aldrich) for 20 h and treated in OptiMEM by different inflammasome activators: ATP (5 mM) or Nigericin (40 μM) for 30 min, MSU (100 μg/mL) or Alum (100 μg/mL) for 6 h. When BMDMs were infected with LPS to induce non-canonical inflammasome activation, there was no difference in caspase-1 activation and IL-1β maturation between WT and Hsp70−/− cells
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