HSP70 and Primary Arterial Hypertension

Abstract

Heat shock protein 70 (HSP70) production is a stress-generated cellular response with high interspecies homology. HSP70 has both chaperone and cytokine functions and may induce, depending on the context, tolerogenic anti-inflammatory reactivity or immunogenic and autoimmune reactivity. Intracellular (chaperoning transit of antigens to MHC in antigen-presenting cells) and extracellular HSP70-related effects are associated with hypertension, which is an inflammatory condition recognized as the most important risk factor for cardiovascular disease mortality. Here, we review (a) the relationship between HSP70, inflammation and immune reactivity, (b) clinical evidence relating to stress, HSP70 and anti-HSP70 reactivity with primary hypertension and (c) experimental data showing that salt-sensitive hypertension is associated with delayed hypersensitivity to HSP70. This is a consequence of anti-HSP70 reactivity in the kidneys and may be prevented and corrected by the T-cell-driven inhibition of kidney inflammation triggered by specific epitopes of HSP70. Finally, we discuss our postulate that lifelong stress signals and danger-associated molecular patterns stimulate HSP-70 and individual genetic and epigenetic characteristics determine whether the HSP70 response would drive inflammatory immune reactivity causing hypertension or, alternatively, would drive immunomodulatory responses that protect against hypertension.

Keywords: HSP70; hypertension; immune reactivity; inflammation.

Figure 1

Immune reactivity induced by HSP70. HSP70 response to stress may induce tolerogenic anti-inflammatory responses as well as immune reactivity. Intracellular HSP70 activation suppresses NLRP3 inflammasome activation. In addition, specific polypeptide sequences of HSP70 induce a tolerogenic responses characterized by IL-10 immunomodulatory secretion. In contrast, extracellular HSP70 induce immune reactivity that includes anti-HSP70 antibody formation. The chaperoning function of HSP70 include the protection and transfer of exogenous and endogenous antigenic peptides to the MHC I and II and the subsequent adaptive immune reactivity. Tolerogenic responses to intracellular HSP70 in dendritic cells and macrophages include reduction of TNFα and INFα and production of IL-10 by T cells. Suppression of T cell-induced inflammatory responses is independent of its effects on monocyte-derived immature dendritic cells [17].

Figure 2

Autoimmunity in primary hypertension. Autoimmune reactivity is a central characteristic of primary hypertension. Prohypertensive immune reactivity has been demonstrated in the arterial adventitial layers, in the tubulointerstitial areas of the kidney and in central and sympathetic nervous systems. PVR: éripheral vascular resistance; CO: cardiac output.

Figure 3

HSP70 immune reactivity and hypertension. (A) Immunization with a specific amino acid sequence * (59) of Mycobacterium tuberculosis HSP70 in the foot pads followed by intrarenal plasmid-delivered administration of HSP70 results in tubulointerstitial inflammation and salt-sensitive hypertension (SSHTN). (B) The induction of immune tolerance with the intraperitoneal administration of the antigenic sequence used to induce immune reactivity results in prtection against SSHTN. (C) Adoptive transfer of T cells obtained from rats tolerized to HSP70 corrects hypertension. (Data from Reference [59]).

Figure 4

Stress-induced HSP70 overexpression and blood pressure. (A) We posit that biological stress induces overexpression of HSP70 that, depending on genetic and epigenetic determinants, induces or suppresses immune reactivity that drives or prevents hypertension. Adverse effects of hypertension are associated with inflammation. The potential role of interaction between HSP70 and Siglec-5 and Siglec-14 is discussed in the text. (B) Increased incidence of fatal and non-fatal cardiovascular outcomes is associated with 24 h mean arterial pressure of 92 mmHg or higher (Figure 4B was published as Figure 1A in the open access paper of Melgarejo JD et al. [66]).