The oxidation of HSP70 is associated with functional impairment and lack of stimulatory capacity

Abstract

Expression of intracellular HSP70 is associated with cytoprotective effects against a wide range of stressful stimuli, such as inflammation, oxidative stress, hypoxia, endotoxins, infections, and fever. This cytoprotective effect is mainly attributed to their ability to stabilize protein structures through chaperone-like reversible interactions. HSP70 was recently detected in the extracellular medium, and its presence in serum is commonly associated with pathological situations, where it exerts modulatory effects on cells of the immune system. Previously, we have described the relationship between serum HSP70 levels, oxidant status, and clinical outcome of septic patients; the group of patients with higher prooxidant status and higher serum HSP70 had also higher mortality. To investigate the possible association between oxidized HSP70 and cytoprotection or cell death, we incubated RAW 264.7 macrophages with oxidized HSP70 and evaluated nitrite production, cell proliferation, cell viability, TNF-α release, and phagocytic activity. We also evaluated structural modifications caused by oxidation in purified HSP70. Oxidation of HSP70 altered its protein structure; besides, the modulatory effect of oxidized HSP70 on RAW264.7 cells was different from that of native HSP70. Macrophages treated with oxidized HSP70 presented lower proliferation and viability, lower phagocytic activity, and lower TNF-α release. These results indicate that oxidation of extracellular HSP70 modified its signaling properties, causing alterations on its modulatory effects on macrophage function and viability.

Putative model for heat shock protein 70 complexation with receptor of advanced glycation end products through fluorescence proximity assays and normal mode analyses

“…Moreover, increased levels of oxidative stress were also associated with increased HSP70 levels in serum in patients who died. Our previous studies (Grunwald et al 2014) showed that macrophages treated with preoxidized HSP70 exhibited a different pattern of activation compared with that of macrophages treated with HSP70, with lower cell proliferation and viability, lower levels of TNF-α release, and lower phagocytic activity. Similar results, including increased secretion of TNF-α and increased phagocytosis, have been observed in macrophages upon RAGE ligand binding (Fujiya et al 2014;Ma et al 2012;Tang et al 2010), suggesting that RAGE may have unidentified interactions associated with specific signaling pathways.…”

The Effects and Mechanism of miR-92a and miR-126 on Myocardial Apoptosis in Mouse Ischemia-Reperfusion Model

“…Researches have showed that HSP70 participates in the regulation of cell apoptosis [31]. HSP70 is a highly conserved protein which protects cell from severe environment, physical, and chemical harm [32,33].…”

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

“…eHSP are more susceptible to oxidative stress in the extracellular space, such as the bloodstream [138]. For instance, the increased protein oxidation in serum observed in AD [144] was associated with the functional impairment of HSP70 [151]. Moreover, oxidized protein aggregates may remain in extracellular fluids in the form of soluble aggregates and stimulate neutrophils to produce high levels of ROS and thereby promoting oxidative stress [27] and the activation of immune-inflammatory responses [152].…”