Stress proteins and initiation of immune response: chaperokine activity of hsp72

Abstract

From its original description as solely an intracellular molecular chaperone, heat shock proteins have now been shown to function as initiators of the host's immune response. Although the exact mechanism by which intracellular heat shock proteins leave cells is still incompletely understood, recent work from several labs suggest that heat shock proteins are released by both passive (necrotic) and active (physiological) mechanisms. Binding to specific surface receptors is a prerequisite for the initiation of an immune response. To date, several cell surface proteins have been described as the receptor for seventy kilo-Dalton heat shock protein (Hsp70) including Toll-like receptors 2 and 4 with their cofactor CD14, the scavenger receptor CD36, the low-density lipoprotein receptor-related protein CD91, the C-type lectin receptor LOX-1, and another member of the scavenger super-family SR-A plus the co-stimulatory molecule, CD40. Binding of Hsp70 to these surface receptors specifically activates intracellular signaling cascades, which in turn exert immunoregulatory effector functions; a process known as the chaperokine activity of Hsp70. This review will highlight recent advances in understanding the mechanism by which Hsp70 initiates the host's immune response.

Figure 1

Schematic representation of stress-induced release of eHsp72. Stress (lightning blot) activates at least three pathways that result in the release of Hsp72 into the circulation. First, if trauma to the cell is overwhelming stress will activates the death pathway either by necrosis or apoptosis and Hsp72 is released from the cell. Second, stress can activate the stress response by triggering the trimerization and nuclear translocation of cytoplasmic HSF-1 (brown rods) to the heat shock element (HSE) and subsequent transcription of Hsp72 (stars). The increased intracellular Hsp72 chaperones peptides (Hsp72-peptide complex) and protects the cell from cell death under certain conditions. The Hsp72-peptide complex is expressed on the cell surface and released into the extracellular milieu within exosomes; Hsp72-exosomes (yellow circle). Hsp72-peptide complexes (Hsp72-pc) and Hsp72-exosomes (Hsp72-ex) make their way into the circulation and can be measured by classical sandwich ELISA. Antigen presenting cells bind and internalize Hsp72-pc and Hsp72-ex. Binding to specific receptors mediated a signal transduction cascade that results in the initiation of an immune response characterized by the upregulation of pro-inflammatory cytokines, chemokines, nitric oxide and costimulatory molecules. Internalization of Hsp72-pc and Hsp72-ex allows the peptides to be processed and presented in the context of MHC class I to cytotoxic T lymphocytes (CTL). CTL's become activated and will recognize and destroy cells presenting the specific peptide. Circulating Hsp72-ex induces NK cells migration and the expression of Hsp72-pc on the surface of stressed cells activates NK lytic functions. Thirdly, stress in form of physical of psychological stress will stimulate the release of Hsp72-pc and Hsp72-ex into the circulation by a hitherto unknown mechanism and by a yet to be discovered tissue/organ.