Current Immunology Reviews (Discontinued) - Volume 13, Issue 1, 2017

Organisms are constantly exposed to acute and chronic stress conditions, which challenge the maintenance of protein homeostasis. Heat Shock Proteins (HSPs) function as molecular chaperones to stabilize protein structures, facilitate refolding of misfolded proteins, and prevent uncontrolled protein aggregation. Therefore, HSPs serve as the first and last line of defense in the events of proteotoxic stresses. The stress-inducible expression of HSPs, which is a hallmark of the heat shock response, is under strict control of evolutionarily conserved transcription factors, known as Heat Shock Factors (HSFs). Invertebrates have only a single HSF, whereas the HSF family in vertebrates consists of multiple members. Direct interactions of HSFs with various proteins, including HSPs, chromatinassociated proteins, and other HSF family members as well as their complex post-translational modifications, allow these transcription factors to function not only in stress responses but also in many other biological processes. For example, mammalian HSF1, HSF2, and HSF4 are fundamental for normal organismal development and healthy aging. Moreover, recent discoveries have highlighted the importance of HSFs in tumorigenesis, neurodegeneration, and metabolic disorders, which positions them as promising therapeutic targets in multiple human diseases. In this review, we focus on recent advances in the HSF biology and discuss the functional impact of HSFs on stress responses, development, aging, and age-related pathologies.

The 60 kDa heat shock chaperonin protein 60 (Hsp60 or Cpn60) is highly conserved in evolution and present in nearly all organisms. Eukaryotic paralogues are nuclear encoded but act in certain intra- and extracellular compartments including venous blood. HSP60s function as ATP-dependent molecular chaperones and collaborate with further chaperones to perform their duties. While intracellular HSP60s are crucially involved in proteostasis as well as pro-apoptotic and pro-survival pathways, membrane-bound and extracellular HSP60s are thought to function as danger signals to the immune system and act as powerful immune mediators. HSP60s are released into the peripheral blood from healthy subjects and under a variety of pathological conditions, including cardiovascular diseases and cancer. Hsp60 levels successively rise or decline during tumorigenesis in diverse organs. Hsp60 over-expression in cancer cells stimulates cell proliferation, blocks senescence as well as stress-induced apoptosis, and facilitates oncogenic transformation. This chaperone might thus have future applicability as biomarker for diagnosis and assessing prognosis or response to therapeutic intervention. Hsp60 chaperonopathies represent the basis for targeting Hsp60 for the development of novel agents affecting its activity. This review summarizes recent knowledge and new perspectives on the Hsp60 chaperone machinery and its role in disease and therapy.

HSP60 participates in many interactions between the system integrated by all chaperones and closely associated molecules (chaperoning system or CS) and the immune system (IS). These interactions occur constantly to maintain normal cell physiology but, occasionally, they are perturbed and become mediators of pathologic events that may lead to disease. This switch to pathology may be initiated by various factors, genetic or acquired, which cause qualitative and/or quantitative modifications of HSP60, or immune crossreactivity between the human and microbial chaperonin orthologs, or a break in the balance between the pro- and anti-inflammatory actions of the chaperonin. Thus, autoimmune and chronic inflammatory pathologies may occur. Likewise, a perturbation of the CS-IS interactions, e.g., those that take place during ageing, may favor carcinogenesis. HSP60 may be commandeered by tumor cells to assist its high-rate protein synthesis and, also, to be an emissary among the devices tumor cells utilize to avoid anti-tumor immune reactions. Here, we briefly discuss the canonical and non-canonical functions of HSP/chaperones; and HSP60 as a multifunctional molecule, its migration itinerary, and its possible roles during carcinogenesis and in certain chronic inflammatory and autoimmune diseases. We examine the potential of HSP60 as a biomarker useful for diagnosing and monitoring the progression of the various conditions in which it actively participates. Lastly, we discuss the use HSP60 as target for controlling its activity when it is an etiopathogenic factor, or as a therapeutic agent to correct its deficiency.

The stress-inducible heat shock protein 70 (HSP70) contributes to the cellular stress response that protects cells from adverse environmental conditions. HSP70 can block apoptosis and other types of cell death induced by various stimuli. In malignant cells, the expression of HSP70 is frequently elevated and some cancers even depend on HSP70 overexpression to maintain their malignant phenotype. Extracellular HSP70 in contrast, provides a danger signal to the immune system and may activate anti-tumor immune responses by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. HSP70-activated NK cells, for example, can attack tumor cells that express HSP70 at the plasma membrane. This feature of HSP70 reminds of other stress-inducible molecules including the major histocompatibility complex (MHC) class I chain-related molecules A (MICA) and B (MICB), which are ligands for activating NK receptor NK group 2, member D (NKG2D) and are induced by cellular and genotoxic stress on many tumor cells. Interestingly, the stress-inducible HSP70 and stressinducible NKG2D ligands can collaborate in tumor immunosurveillance by NK cells. HSP70-activated NK cells can also kill tumor cells that express NKG2D ligands at the plasma membrane instead of HSP70. An adaptive cellular immunotherapy with autologous HSP70-stimulated NK cells may therefore target not only tumors that express HSP70 at the plasma membrane but also those that express NKG2D ligands. Notably, an overexpression of HSP70 in tumors usually fails to protect against apoptosis executed in the granule exocytosis pathway of CTL and NK cells, making immunotherapies attractive to treat HSP70-overexpressing malignancies.

Heat shock proteins (HSPs) play an important role in innate immune function of the intestinal mucosa and in the barrier function of intestinal epithelial cells. Among the HSPs expressed in epithelial cells, as well as cells of the innate immune system is Grp94/Gp96. Differences in protein expression of Gp96 have been observed in patients with inflammatory bowel disease (IBD), suggesting that this chaperone may be important in this pathology. The role that Gp96 plays seems to be different depending on the cell type where it is expressed. In epithelial cells, Gp96 is recognized by pathogenic bacteria and allows bacterial invasion and translocation. Gp96 is also increased in the epithelium of patients with Crohn's disease (CD) when compared with healthy subjects. In macrophages, where it is absent in IBD patients, Gp96 plays important role in the regulation of pro-inflammatory cytokines and the functionality of several receptors, such as Toll-like receptors, whereas in dendritic cells it is involved in cell maturation. The therapeutic effect of Gp96 has been reported in animal models of disease, where its exogenous administration ameliorated colitis and reduced tumor growth and metastasis, and increased the survival of mice. Of interest, the efficacy of Gp96 as a therapeutic vaccine is currently being evaluated in clinical trials with modest antitumor effects. Given the increasing evidence of the potential therapeutic effect of this chaperone, in this review we will highlight the

Heat Shock Proteins (HSPs) are a group of highly conserved molecular chaperones that play important roles in homeostasis and the cellular response to stress. In the cardiovascular system, HSPs maintain vessel wall integrity and cardiomyocyte function; they may be upregulated and translocated to the cell surface in response to environmental stressors. HSPs contribute to the inflammatory processes that mediate the development of atherosclerosis by activating the innate and adaptive immune response. Misdirected autoimmune attack of surface HSPs on stressed vascular endothelial cells by circulating anti-Hsp60 antibodies lead to damage of the vessel wall and atherogenesis. Additionally, other HSPs contribute to the pro-inflammatory state in the vessel wall by stimulating macrophages and reactive Tcells to release cytokine and chemotactic factors. Atrial Fibrillation (AF) is closely related to atherosclerotic burden and changes to levels of various HSPs have been associated with increased incidence of AF in stressed cardiomyocytes after ischemia reperfusion injury. Modulation of HSP expression may be a useful therapeutic strategy in the management of atherosclerosis and AF.

Diabetes is a severe metabolic disorder characterized by hyperglycemia due to defects in insulin secretion and/or insulin action. Over the past decades, a continuous rise of the incidence of diabetes is observed, leading to epidemic dimensions of the disease in large parts of the western world. Depending on the type of diabetes, (auto-)immune processes (type 1 diabetes) or metabolic disorders (type 2 diabetes) dominate the pathogenesis of the disease. Therefore, investigations aiming at the identification of disease mechanisms and the development of preventive and therapeutic approaches, focus on the identification of common regulators of both immunologic and metabolic pathways involved in the pathogenesis of diabetes. So far, extensive research, employing clinical and experimental approaches demonstrate a central role of heat shock proteins (HSPs) in diabetes development. In type 1 diabetes intracellular HSPs located in the beta cell can provide efficient protection against the deleterious effects of autoimmune effector mechanisms whereas extracellular HSPs can stimulate the release of beta cell damaging mediators from innate immune cells or even contribute to the induction of immune reactivity against beta cell specific antigens. In type 2 diabetes HSPs are involved in the control of various immunologic and metabolic processes contributing to the induction and maintenance of low-grade, subclinical inflammation associated with the development of diabetes and related disorders such obesity and insulin resistance. The results of current research on the pathogenesis of diabetes point to HSPs and HSP-dependent immunologic and metabolic pathways as promising targets for strategies to prevent or cure diabetes and its sequelae.

Historically, heat shock proteins were seen foremost as playing roles in stress protection and short term adaption to changing environmental parameters. This view is now superseded by findings that implicate HSPs in various aspects of cell regulation, protein maturation and modulation, immune response and immune modulation. Likewise in parasitic protozoa, the old view of HSPs as protecting the pathogens against the harsh conditions inside mammalian hosts has given way to a far broader picture in which parasite HSPs play decisive regulatory roles in primitive protozoa, regulating cell cycle, life cycle, morphology and protein trafficking and thus affecting viability, infectivity, virulence and host immune responses. In this review, we discuss the impact of Leishmania heat shock proteins on viability and survival inside mammalian host organisms.