Hsp70 and cardiac surgery: molecular chaperone and inflammatory regulator with compartmentalized effects

Abstract

Open heart surgery is a unique model to study the interplay between cellular injury, regulation of inflammatory responses and tissue repair. Stress-inducible heat shock protein 70-kDa (Hsp70) provides a molecular link between these events. In addition to molecular chaperoning, Hsp70 exerts modulatory effects on endothelial cells and leukocytes involved in inflammatory networks. Hsp70 residing in the intracellular compartment is part of an inhibitory feedback loop that acts on nuclear factor kappaB (NF-kappaB). In contrast, extracellular Hsp70 is recognized by multiple germline-encoded immune receptors, e.g., Toll-like receptor (TLR) 2, TLR4, LOX-1, CD91, CD94, CCR5 and CD40. Hsp70 is thereby able to enhance chemotaxis, phagocytosis and cytolytic activity of innate immune cells and stimulate antigen-specific responses. These apparent contradictory pro- and anti-inflammatory effects of endogenous Hsp70 in the context of cardiac surgery are still not fully understood. An all-embracing model of the compartmentalized effects of endogenous Hsp70 in the orchestration of inflammatory responses in cardiac surgery is proposed.

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

“…Hsp70 is generally accepted as a good marker for effective Hsp90 inhibition as its increased expression is known to result from Hsp90 blockade-induced activation and nuclear translocation of the transcription factor heat shock factor-1, which then drives the synthesis of this chaperone (Dakappagari et al 2010;Collins et al 2013). Hsp70, in turn, is also regarded as a potent negative regulator of inflammatory responses through, but not limited to, its negative feedback effect on NFκB signaling activity (de Jong et al 2009;Stocki and Dickinson 2012). This suggests that, in addition to Hsp90 inhibition per se, Hsp70 itself may account for the anti-inflammatory effects seen in our study and warrants further investigation.…”

Extracellular Heat Shock Protein 70 Induces Cardiomyocyte Inflammation and Contractile Dysfunction via TLR2

“…9-11, 22 Overexpressed intracellular HSP70 has shown to reduce infarct size and preserve cardiac contractility in several animal myocardial infarction models. 35-37 However, DAMPs are also released extracellularly and appear to have very different effects; many of these effects mediated through innate immune receptors.…”

“…16,19, 22 Increased expression of ICAM-1 in response to inflammatory stimuli has been shown to reduce cardiac contractility, 27,28,47 therefore, we used ICAM-1 as an important measure of inflammation to assess whether mice deficient in TLR2 or TLR4 could mount a response to HSP70. TLR4 knockout cardiomyocytes increased ICAM-1 expression following exposure to HSP70 to the same extent as wild-type cardiomyocytes, suggesting that HSP70 does not appreciably signal via TLR4.…”

“…Therefore, we tested for a direct effect of HSP70 on cardiomyocyte inflammatory and contractile function. In immune cells 16, 20 and endothelial cells, 21,22 HSP70 is a ligand for TLRs. In the heart, TLR2 and TLR4 are most prominently involved following ischemia-reperfusion MATHUR S et al…”

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

“…82,83 Furthermore, HSP70 has been indicated to have a negative feedback effect on NF-kB signaling activity. 84 HSP70 has also been demonstrated to switch off TNF receptor-associated factor 6. 85 Active lupus renal disease can be defined clinically or pathologically.…”