Heat Shock Proteins HSP27 and HSP70 Are Present in the Skin and Are Important Mediators of Allergic Contact Hypersensitivity

Abstract

Proteomic analysis of murine skin has shown that a variety of heat shock proteins (HSPs) are constitutively expressed in the skin. Using murine allergic contact hypersensitivity as a model, we investigated the role of two heat shock proteins – HSP27 and HSP70 – in the induction of cutaneous cell-mediated immune responses. Immunohistochemical examination of skin specimens showed that HSP27 was present in the epidermis and HSP70 was present in both the epidermis and dermis. Inhibition of HSP27 and HSP70 produced a reduction in the DNFB contact hypersensitivity response and resulted in the induction of antigen specific unresponsiveness. Treatment of dendritic cell cultures with recombinant HSP27 caused in the upregulation of IL-1β, TNF-α, IL-6, IL-12p70 and IL-12p40 but not IL-23p19, which was inhibited when antibodies to HSP27 were added. DNFB conjugated dendritic cells that had been treated with HSP27 had an increased capacity to initiate contact hypersensitivity responses compared to control dendritic cells. This augmented capacity required TLR4 signaling because neither cytokine production by dendritic cells nor the increased induction of contact hypersensitivity responses occurred in TLR4 deficient C3H/HeJ mice. Our findings indicate that a cascade of events occurs following initial interaction of hapten with the skin that includes increased activity of heat shock proteins, their interaction with TLR4 and, in turn, increased production of cytokines that are known to enhance antigen presentation by T-cells. The results suggest that heat shock proteins form a link between adaptive and innate immunity during the early stages of contact hypersensitivity.

Human Myocardium Releases Heat Shock Protein 27 (HSP27) after Global Ischemia: The Proinflammatory Effect of Extracellular HSP27 through Toll-like Receptor (TLR)-2 and TLR4

“…It is reported that recombinant HSP27 induces cytokine production in bone marrow-derived dendritic cell and that its effect is attenuated in cells from TLR4 mutant mice (43). This study suggests that TLR4 is one of the signaling pathways involved in mediating the proinflammatory effect of extracellular HSP27.…”

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

“…Reduced production of CXCL1 and GM-CSF has also been shown in RAS transformed MyD88-deficient keratinocytes as compared to RAS transformed WT cells [62]. Constitutive mediator production of keratinocytes in vitro might be induced by components of the keratinocyte medium, as for example EGF can induce GM-CSF [63] [30,66,67]. Thus keratinocytes may serve as danger sensors in the skin and can also contribute to local inflammation either directly or indirectly by activating T cells through the induction of proinflammatory mediators.…”

“…Constitutive mediator production of keratinocytes in vitro might be induced by components of the keratinocyte medium, as for example EGF can induce GM-CSF [63], or may be explained by the fact that in vitro differentiated keratinocytes show an inflammatory phenotype [64]. MyD88 signaling in keratinocytes might be activated by PAMPs of the microflora or DAMPs such as hyaluronic acid fragments, heat shock proteins (HSP), or high-mobility group protein B1 (HMGB1), which signal via TLR [65] and were shown to be induced upon skin damage [30,66,67]. Thus keratinocytes may serve as danger sensors in the skin and can also contribute to local inflammation either directly or indirectly by activating T cells through the induction of proinflammatory mediators.…”

The Antioxidative Effect of Heat‐Shock Protein 70 in Dendritic Cells

“…Yusuf et al [42] reported that topically applied anti-HSP70 antibody had a suppressive effect on CHS by inhibition of inflammatory cytokines. Although HSP70 was found intracellularly, the secreted extracellular form of HSP70 was also recognized [43,44].…”