Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease.

/pdf/cytokines-in-atherosclerosis-pathogenic-and-regulatory-k5l4m0ggqp.pdf

Cytokines in atherosclerosis: pathogenic and regulatory pathways.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(03)14075-5.pdf

Heat shock proteins as regulators of the immune response

The 70-kDa heat shock protein (HSP70) family of molecular chaperones represents one of the most ubiquitous classes of chaperones and is highly conserved in all organisms. Members of the HSP70 family control all aspects of cellular proteostasis such as nascent protein chain folding, protein import into organelles, recovering of proteins from aggregation, and assembly of multi-protein complexes. These chaperones augment organismal survival and longevity in the face of proteotoxic stress by enhancing cell viability and facilitating protein damage repair. Extracellular HSP70s have a number of cytoprotective and immunomodulatory functions, the latter either in the context of facilitating the cross-presentation of immunogenic peptides via major histocompatibility complex (MHC) antigens or in the context of acting as "chaperokines" or stimulators of innate immune responses. Studies have linked the expression of HSP70s to several types of carcinoma, with Hsp70 expression being associated with therapeutic resistance, metastasis, and poor clinical outcome. In malignantly transformed cells, HSP70s protect cells from the proteotoxic stress associated with abnormally rapid proliferation, suppress cellular senescence, and confer resistance to stress-induced apoptosis including protection against cytostatic drugs and radiation therapy. All of the cellular activities of HSP70s depend on their adenosine-5'-triphosphate (ATP)-regulated ability to interact with exposed hydrophobic surfaces of proteins. ATP hydrolysis and adenosine diphosphate (ADP)/ATP exchange are key events for substrate binding and Hsp70 release during folding of nascent polypeptides. Several proteins that bind to distinct subdomains of Hsp70 and consequently modulate the activity of the chaperone have been identified as HSP70 co-chaperones. This review focuses on the regulation, function, and relevance of the molecular Hsp70 chaperone machinery to disease and its potential as a therapeutic target.

/pdf/the-human-hsp70-family-of-chaperones-where-do-we-stand-3i2v7sflty.pdf

The human HSP70 family of chaperones: where do we stand?

This review discusses the structure and function of molecular chaperones, with emphasis on their role in rescuing misfolded proteins. It also includes a discussion of the diseases in which abnormalities of these caretaker molecules or their molecular partners have been found.

Sick chaperones, cellular stress, and disease.

Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0313153

Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation.

Although primarily regarded as being intracellular, this study has identified the presence of heat shock protein 60 (Hsp60) in the peripheral circulation of normal individuals. The median Hsp60 concentration was approximately 3.5-fold higher in females than in males and significantly higher levels of anti-human Hsp60 antibodies were also detected in females. There were no differences in the levels of antibodies to mycobacterial Hsp60 between males and females, nor did antibody levels correlate with Hsp60 concentrations. Hsp60 was not released from mitogenically stimulated peripheral blood mononuclear cells. The potential physiological roles for circulating Hsp60 are unknown. Given the emerging evidence that inappropriate reactivity to heat shock proteins is involved in autoimmune disease and that T cells responsive to self Hsp60 appear to be protective, these findings suggest that circulating Hsp60 may be involved in the regulation of tolerance to self and immunity to bacterial forms of these widely expressed and structurally conserved proteins.

Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals.

Heat shock proteins (Hsp) are families of phylogenetically conserved molecules that have a range of cytoprotective and intracellular functional roles. Reactivity to heat shock proteins has been implicated in the development of autoimmune disease and tissue expression of heat shock proteins and increased levels of anti-Hsp antibodies have also been reported in vascular disease. This study compared circulating levels of Hsp60 and Hsp70 and antihuman Hsp60, antihuman Hsp70, and antimycobacterial Hsp65 antibodies in peripheral (PVD) and renal (RVD) vascular disease with those in age- and sex-matched controls. Levels of Hsp70 were higher in both PVD (median 580 vs 40; P < 0.01) and RVD (median 160 vs 0; P < 0.03), whereas there were no differences in Hsp60 levels. Anti-Hsp60 antibody levels were elevated in PVD (146 vs 81 arbitrary units/ml; P < 0.04), but not RVD. This is the first study to demonstrate increased levels of circulating Hsp70 in pathological disease states; however, its physiological role remains to be determined.

Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease.

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Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals.

Elevated levels of circulating heat shock protein 70 (Hsp70) in peripheral and renal vascular disease.