Molecular chaperones and heat shock proteins in atherosclerosis

In response to stress stimuli, mammalian cells activate an ancient signaling pathway leading to the transient expression of heat shock proteins (HSPs). HSPs are a family of proteins serving as molecular chaperones that prevent the formation of nonspecific protein aggregates and assist proteins in the acquisition of their native structures. Physiologically, HSPs play a protective role in the homeostasis of the vessel wall but have an impact on immunoinflammatory processes in pathological conditions involved in the development of atherosclerosis. For instance, some members of HSPs have been shown to have immunoregulatory properties and modification of innate and adaptive response to HSPs, and can protect the vessel wall from the disease. On the other hand, a high degree of sequence homology between microbial and mammalian HSPs, due to evolutionary conservation, carries a risk of misdirected autoimmunity against HSPs expressed on the stressed cells of vascular endothelium. Furthermore, HSPs and anti-HSP antibodies have been shown to elicit production of proinflammatory cytokines. Potential therapeutic use of HSP in prevention of atherosclerosis involves achieving optimal balance between protective and immunogenic effects of HSPs and in the progress of research on vaccination. In this review, we update the progress of studies on HSPs and the integrity of the vessel wall, discuss the mechanism by which HSPs exert their role in the disease development, and highlight the potential clinic translation in the research field.     

Neutrophils that infiltrate the central nervous system regulate T cell responses

Regulation of inflammatory responses is critical to progression of organ-specific autoimmune disease. Although many candidate cell types have been identified, immunoregulatory activity has rarely been directly assayed and never from the CNS. We have analyzed the regulatory capability of Gr-1high neutrophils isolated from the CNS of mice with experimental autoimmune encephalomyelitis. Proportions of neutrophils were markedly increased in the CNS of IFN-gamma-deficient mice. Strikingly, CNS-derived neutrophils, whether or not they derived from IFN-gamma-deficient mice, were potent suppressors of T cell responses to myelin or adjuvant Ags. Neutrophil suppressor activity was absolutely dependent on IFN-gamma production by target T cells, and suppression was abrogated by blocking NO synthase. These data identify an immunoregulatory capacity for neutrophils, and indicate that interplay between IFN-gamma, NO, and activated Gr-1high neutrophils within the target organ determines the outcome of inflammatory and potentially autoimmune T cell responses.     

Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new?

Juvenile idiopathic arthritis (JIA) is a disease characterized by chronic joint inflammation, caused by a deregulated immune response. In patients with JIA, heat shock proteins (HSPs) are highly expressed in the synovial lining tissues of inflamed joints. HSPs are endogenous proteins that are expressed upon cellular stress and are able to modulate immune responses. In this review, we concentrate on the role of HSPs, especially HSP60, in modulating immune responses in both experimental and human arthritis, with a focus on JIA. We will mainly discuss the tolerogenic immune responses induced by HSPs, which could have a beneficial effect in JIA. Overall, we will discuss the immune modulatory capacity of HSPs, and the underlying mechanisms of HSP60-mediated immune regulation in JIA, and how this can be translated into therapy.     

Regulatory T cell responses: potential role in the control of atherosclerosis

PURPOSE OF REVIEW: Atherosclerosis is an inflammatory disease of the arterial wall where both innate and adaptive Th1-driven immunoinflammatory responses contribute to disease development. Th2-related responses have been shown to be either protective or pathogenic. Thus, it is unclear whether immunoregulatory activity can modulate disease development. RECENT FINDINGS: Novel subtypes of T cells, called the regulatory T cells, have been shown recently to play a critical role in the maintenance of immunological tolerance against self and non-self antigens and prevent the development of various immunoinflammatory diseases. Preliminary studies suggest a potential role for this type of regulatory T cell response in atherosclerosis. SUMMARY: Here we present a novel view of the immunoinflammatory response in atherosclerosis where natural and/or adaptive regulatory T cell responses modulate both Th1 and Th2 pathogenic responses and play a central role in counteracting disease initiation and progression.     

Activation of the D prostanoid receptor 1 regulates immune and skin allergic responses

The mobilization of Langerhans cells (LCs) from epithelia to the draining lymph nodes is an essential process to initiate primary immune responses. We have recently shown that in mice, PGD2 is a potent inhibitor of epidermal LC emigration. In this study, we demonstrate that activation of the D prostanoid receptor 1 (DP1) impedes the TNF-alpha-induced migration of human LCs from skin explants and strongly inhibits the chemotactic responses of human LC precursors and of maturing LCs to CC chemokine ligands 20 and 19, respectively. Using a murine model of atopic dermatitis, a chronic Th2-type allergic inflammatory disease, we demonstrate that the potent DP1 agonist BW245C dramatically decreases the Ag-specific T cell activation in the skin draining lymph nodes and markedly prevents the skin lesions following repeated epicutaneous sensitization with OVA. Interestingly, analysis of the local response indicates that BW245C treatment strongly reduces the recruitment of inflammatory cells into the dermis and disrupts the Th1/Th2 balance, probably through the increased production of the immunoregulatory cytokine IL-10, in the skin of sensitized mice. Taken together, our results suggest a new function for DP1 in the regulation of the immune and inflammatory responses. We propose that DP1 activation by specific agonists may represent a strategy to control cutaneous inflammatory Th2-associated diseases.     

Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function

The ability of mature T lymphocytes to develop effector capacity after encounter with cognate Ag is generally dependent upon inflammatory signals associated with infection that induce dendritic cell activation/maturation. These inflammatory signals can derive directly from pathogens or can be expressed by host cells in response to infection. Heat shock proteins (HSPs) are a class of host-derived inflammatory mediators that perform the dual function of both chaperoning MHC class I-restricted epitopes into the cross-presentation pathway of DCs and inducing the activation/maturation of these DCs to allow priming of cognate CD8(+) T cell effector responses. Although the ability of HSPs to elicit effector CD8 cell responses has been well established, their potential to prime CD4 cell effector responses has been relatively unexplored. In the current study we compared the ability of the endoplasmic reticulum-resident HSP gp96 to prime CD4 vs CD8 cells using TCR transgenic adoptive transfer systems and soluble gp96-peptide complexes. As expected, gp96 facilitated the cross-presentation of a class I-restricted peptide and priming of effector function in cognate CD8 cells. Interestingly, gp96 also facilitated the in vivo presentation of a class II-restricted peptide; however, the resulting CD4 cell response did not involve the development of effector function. Taken together, these data suggest that gp96 is an inflammatory mediator that selectively primes CD8 cell effector function.     

Neural immune pathways and their connection to inflammatory diseases

Inflammation and inflammatory responses are modulated by a bidirectional communication between the neuroendocrine and immune system. Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate. The CNS signals the immune system through hormonal pathways, including the hypothalamic-pituitary-adrenal axis and the hormones of the neuroendocrine stress response, and through neuronal pathways, including the autonomic nervous system. The hypothalamic-pituitary-gonadal axis and sex hormones also have an important immunoregulatory role. The immune system signals the CNS through immune mediators and cytokines that can cross the blood-brain barrier, or signal indirectly through the vagus nerve or second messengers. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This review discusses neuroimmune interactions and evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis.     

Heat shock proteins protect platyfish (Xiphophorus maculatus) from Yersinia ruckeri induced mortality

The significant disadvantages accompanied with the use of antibiotics in aquaculture, emphasize the need for developing alternative disease control strategies, like novel vaccine approaches and immunostimulating measures. Several studies have already pointed out the ability of heat shock proteins (HSPs) to modulate innate and adaptive immune responses, what makes them potent candidates for the development of a new disease prevention method. In this study, the use of self and non-self heat shock proteins as a new prophylactic treatment against bacterial diseases in freshwater aquaculture was investigated. Therefore, an infection model was developed with platyfish as a host for Yersinia ruckeri infections. In this infection model, the effect of different treatments with HSPs on the survival of the fish after bacterial infection was tested: non-lethal heat shock, intracoelomal injection with two recombinant bacterial HSPs, GroEL and DnaK, and a combination of a non-lethal heat shock and an injection with bacterial HSPs. The results show that a non-lethal heat shock could not protect fish against a subsequent infection with Y. ruckeri. However, when the fish received an injection with bacterial HSPs, Y. ruckeri induced mortality was reduced. This effect became significant when the administration of bacterial HSPs was combined with a non-lethal heat shock. These data suggest a possible role for heat shock proteins as an immunostimulating treatment in fish against bacterial infections.     

Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta

Experimental autoimmune encephalomyelitis is a well-characterized model of cell-mediated autoimmunity. TLRs expressed on APCs recognize microbial components and induce innate immune responses, leading to the elimination of invading infectious agents. Certain TLR agonists have been reported to have adjuvant properties in CNS autoimmune inflammatory demyelination. We report in this study that TLR3 stimulation by polyinosinic-polycytidylic acid, a double-stranded RNA analog, suppresses relapsing demyelination in a murine experimental autoimmune encephalomyelitis model. Disease suppression is associated with the induction of endogenous IFN-beta and the peripheral induction of the CC chemokine CCL2. These data indicate that a preferential activation of the MyD88-independent, type I IFN-inducing TLR pathway has immunoregulatory potential in this organ-specific autoimmune disease.     

Can the stress protein response be controlled by ‘membrane-lipid therapy’?

In addition to high temperature, other stresses and clinical conditions such as cancer and diabetes can lead to the alteration of heat-shock protein (HSP) levels in cells. Moreover, HSPs can associate with either specific lipids or with areas of special membrane topology (such as lipid rafts), and changes in the physical state of cellular membranes can alter hsp gene expression. We propose that membrane microheterogeneity is important for regulating the HSP response. In support of this hypothesis, when particular membrane intercalating compounds are used to alter membrane properties, the simultaneous normalization of dysregulated expression of HSPs causes beneficial responses to disease states. Therefore, these compounds (such as hydroxylamine derivatives) have the potential to become a new class of pharmaceuticals for use in 'membrane-lipid therapy'.     

Are heat shock proteins therapeutic target for Parkinson's disease?

Heat shock proteins (HSPs), known as molecular chaperone to assist protein folding, have recently become a research focus in Parkinson's disease (PD) because the pathogenesis of this disease is highlighted by the intracellular protein misfolding and inclusion body formation. The present review will focus on the functions of different HSPs and their protective roles in PD. It is postulated that HSPs may serve as protein folding machinery and work together with ubiquitin-proteasome system (UPS) to assist in decomposing aberrant proteins. Failure of UPS is thought to play a key role in the pathogenesis of PD. In addition, HSPs may possess anti-apoptotic effects and keep the homeostasis of dopaminergic neurons against stress conditions. The critical role of HSPs and recent discovery of some novel HSPs inducers suggest that HSPs may be potential therapeutic targets for PD and other neurodegenerative disorders.     

Heat Shock Protein 70: Roles in Multiple Sclerosis

Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.     

Heat shock protein 70: roles in multiple sclerosis

Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.     

TNF-α Acts as an Immunoregulator in the Mouse Brain by Reducing the Incidence of Severe Disease Following Japanese Encephalitis Virus Infection

Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.     

Stress biomarkers and proteomics alteration to thermal stress in ruminants: A review

Heat stress may adversely affect physiochemical and immune responses of livestock and alter biological functions. The comfort or thermoneutral zone for livestock, which has long been a subject of research, mainly depends on species, breed, and health. Heat stress is associated with impaired livestock productivity due to reductions in feed intake, growth rates and immunity and changes in blood constituents and biological pathways. In ruminants, elevated temperatures have deleterious consequences on protein synthesis. Exposure of ruminant animals to elevated temperatures may induce release of heat shock proteins (HSPs); HSPs usually enter the blood circulation during tissue damage and causes cell necrosis or death. Additionally, hyperthermia is associated with augmented production of cellular reactive oxygen species (ROS), which cause protein degradation and further decrease protein synthesis by preventing protein translation. Moreover, it has been suggested that high environmental temperatures lead to increased inflammatory signalling in tissues via activation of the nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α) pathways as well as via alteration of skin colour gene (melanocortin 1 receptor (MC1R) and premelanosome protein (PMEL)) expression. Previous proteomics analyses have suggested that heat stress can reduce adenosine triphosphate (ATP) synthesis, alter gluconeogenesis precursor supply, and induce lipid accumulation in the liver with subsequent disturbance of liver structure. This review focuses on the scientific evidence regarding the impact of heat stress on immune and inflammatory responses, antioxidant status, stress biomarkers, skin colour gene (PMEL and MC1R) expression and proteomic profiles in ruminants.     

Heat shock proteins HSP70 and GP96: structural insights

Several heat shock proteins (HSPs) act as potent adjuvants for eliciting anti-tumor immunity. HSP-based tumor vaccine strategies have been highly successful in animal models and are undergoing testing in clinical trials. It is generally accepted that HSPs, functioning as chaperones for tumor antigens, elicit tumor-specific adaptive immune responses. HSPs also appear to induce innate immune responses in an antigen-independent fashion. Innate responses generated by HSPs may contribute to anti-tumor immunity. Immunologically active chaperones with anti-tumor activity are referred to as “immunochaperones”. Here, we review the studies that address the role of structural domains or regions of the immunochaperones HSP70 and GP96 that may be involved in the induction of adaptive or innate immune responses. This article forms part of the Symposium in Writing “Thermal stress-related modulation of tumor cell physiology and immune responses”, edited by Elfriede Noessner.     

Cell stress and implications of the heat-shock response in skin

Heat-shock proteins (HSPs), or so-called stress proteins may play an important role in cutaneous pathophysiology. HSPs are a group of highly conserved molecules that are expressed by all cells when subjected to heat or other forms of physical or chemical stress. The physiological roles of stress proteins are varied and are important in stress and nonstress conditions. They bind to other cellular proteins and participate in protein folding pathways during stress and also during the synthesis of new polypeptides. HSPs are also essential for thermotolerance and for prevention and repair of damage caused in DNA after ultraviolet exposure. Although HSPs are expressed in the skin in both epidermis and dermis, HSPs may influence many other cellular processes in the inflammatory and immune skin response. Many authors have speculated on a link between HSPs and human skin disease characterized by inflammation and proliferation.Abbreviations HSP heat-shock protein - IL-1 interleukin-1     

The role of heat shock proteins and their receptors in the activation of the immune system

Heat shock proteins (HSPs) have been described as potent tumor vaccines in animal models and are currently studied in clinical trials. The underlying immune response relies on immunogenic peptides that the HSPs have acquired intracellularly by interfering with the classical antigen processing pathways. There have been numerous reports shedding light on how HSPs are able to gain this function and a number of important requirements for HSP-mediated specific immunity have been described: first, the ability of HSPs to bind immunogenic peptides. Second, the acquisition of HSPs by specialized antigen presenting cells with efficient antigen processing pathways capable of inducing cellular immune responses. Third, the existence of specific receptors on the surfaces of antigen presenting cells, allowing efficient and rapid uptake of HSP-peptide complexes from the extracellular fluid. And fourth, the ability of heat shock proteins to activate antigen presenting cells, enabling the latter to prime cytotoxic T cell responses against the peptides associated to HSPs.