HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway

Gupta, Sanjiv; Knowlton, Anne A

doi:10.1152/ajpheart.01355.2006

Cited by 318 publications

(272 citation statements)

References 24 publications

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“…The HSP60 is a DAMP molecule that can be actively secreted from ischaemic cardiomyocytes through specific pathways dependent on both lipid rafts and exosomes 31. Studies from other labs and ours have showed that ischaemia, either alone or followed by reperfusion, induces marked release of HSP60 from cardiomyocytes, which can activate TLR4 and induce cytokine expression in cardiomyocytes 15, 18, 31, 32. Furthermore, we found HSP60 in the circulation of post‐infarct CHF rats 16.…”

Section: Discussionsupporting

confidence: 52%

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

132

108

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It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.

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Section: Discussionsupporting

confidence: 52%

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

132

108

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“…Circulating large and small heat shock proteins (HSP) are implicated as modulating adaptive and innate immunity in a variety of disease and inflammatory pathologies beyond their defined chaperone effects [1][2][3][4][5][6][7][8]. Large HSP are thought to act as endogenous danger signals augmenting inflammatory cytokines by triggering monocyte (MO) Toll-like receptors (TLR) and scavenger receptors independently of LPS contaminants [6,7,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells

Laudański

Miller-Graziano

2007

Eur J Immunol

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Circulating heat shock protein (HSP)‐27 is associated with tumor progression and increased post‐injury infection. Extracellular HSP‐27 might alter monocyte (MO)‐derived DC and/or MΦ function to mediate immunosuppression. HSP‐27 treatment inhibited expression of CD1a and CD1b/c, antigen uptake, and allogeneic T cell induction (MLR) by IL‐4 + GM‐CSF‐differentiated human DC while increasing some MΦ characteristics (↑CD14, ↑CD16, ↑CD163). MO cytokine receptor profiles elicited by 24‐h exogenous HSP‐27 treatment remained supportive of immature DC (iDC) emergence (↑IL‐4R, ↓IL‐6R, ↓M‐CSFR). IL‐10, IL‐6, and M‐CSF (which promote MΦ differentiation) were significantly increased in IL‐4 + GM‐CSF + HSP‐27 MO→iDC differentiation cultures. However, HSP‐27 treatment during MO differentiation to DC increased programmed cell death ligand 1 coinhibitor and depressed CD86 costimulator expression in parallel to decreased iDC MLR activity. This suggested that increased MΦ differentiation was not solely responsible for HSP‐27 reduction of differentiating DC activity. HSP‐27 treatment actually depressed the phagocytic capacity of MO differentiated to MΦ by IL‐10 or M‐CSF culture. CD163 (hemoglobin receptor) expression was depressed on M‐CSF + HSP‐27 MO‐derived MΦ. HSP‐27‐mediated inhibition of MO→iDC differentiation was reversed by p38α & β inhibitor (SB202190) addition or TLR4 receptor modulation. HSP‐27 impaired appropriate MO→iDC and MO→MΦ differentiation modulating expression of receptors necessary for their proper functions. This suggests that endogenous HSP‐27 has immunoregulatory activities which could contribute to immunopathology.

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“…Hsp60 appears to have both pro-survival and pro-death effects in different cells that have been suggested to be mediated by its interaction with specific proteins in the cytosol such as caspases, Bax, Survivin, p53, ␤-catenin, and IKK (I B kinase) (4 -8). Hsp60 has also been detected on the surface of normal and tumor cells (9 -11), in the extracellular space (12), and even in peripheral blood of healthy subjects (13). The vast amount of information regarding extramitochondrial activities of Hsp60 is confusing especially considering the lack of knowledge on the basic mechanisms of its dual localization and the specific molecular functions outside the organelle.…”

mentioning

confidence: 99%