## 2 Immunomodulatory Function of Extracellular Hsp60, Hsp70, and Hsp90
Hsp90 plays a proinflammatory role through the interaction with its client proteins, such as members of the receptor-interacting protein (RIP) kinases and, thereby, activates the NF-kB pathway. Under physiological conditions, intracellular Hsp90, by blocking heat shock factor (HSF)1, prevents the transcription of Hsp genes, such as Hsp70, or other genes that code for anti-inflammatory molecules. The pharmacological inhibition of Hsp90 can lead to upregulation of the transcription of intracellular Hsp70 and of anti-inflammatory molecules by its release. Abbreviations: MMP, matrix metalloproteinase; TLR, toll-like receptor; IKK, inhibitor of xB kinase; RIP, receptor interaction protein; CD, cluster of differentiation; lkB, inhibitory subunit I kappa B-alpha; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; HSF1, heat shock factor 1; P, phosphate; Hsp, heat shock protein; iNOS, inducible isoform of nitric oxide synthase. CD 25+ T cells (Tregs), leading to an immunosuppressive adaptive response without APC participation [16; 31]. In addition, the chaperone-peptide complexes can also recognize the CD91 receptor of macrophages/dendritic cells and facilitate antigen presentation [28] (Figure 1). The activation of the adaptive response via Hsp70 might represent a negative reaction for the cell, but it could be considered advantageous for the development of immunological memory in preparation for rapid reaction against subsequent insults [32]. In contrast to the proinflammatory function of extracellular Hsp70, intracellular Hsp70 has an anti-inflammatory effect in the brain, especially when overexpressed following brain damage. Thus, Hsp70 can be anti-inflammatory because it can block the expression of proinflammatory molecules, such as matrix metalloproteinases [33], and it can also promote the reduction or the inhibition of NF-kB activity [34; 35] (Figure 1). In addition, intracellular Hsp70 interferes also with genes involved in various neuronal pathways such as transmission of nerve impulses [36]. Therefore, extracellular Hsp70 could in principle have anti-inflammatory and neuroprotective effects similar to those of the intracellular counterpart [37]. Consequently, it is likely that an increase of intracellular Hsp70 will lead to an increase of functional extracellular Hsp70, contributing to the reduction of the inflammation associated with neurodegeneration. Pharmacological increase of the Hsp70 level in neurons and microglia by 17-N-allyamino-17-demethoxygeldanamycin (17-AAG) reduced the hemorrhagic volume in a mouse model of traumatic brain injury [38]. Likewise, 17-AAG inhibition of Hsp90 induced the expression of Hsp70 and Hsp60 [39]. Thus, it may be said that Hsp70, Hsp60, and Hsp90 promote inflammatory responses and, consequently, neuronal damage and are implicated in neuroinflammation and neurotoxicity. Cytosolic Hsp60 has been shown to directly interact with the inhibitor of xB kinase (IKK), promoting activation of NF-kB-dependent gene transcription by tumor necrosis factor-\(\alpha\) (TNF\(\alpha\)) [40] (Figure 1). Hsp90 can induce a proinflammatory response in different ways, for example, by sequestering the regulator transcriptional factor heat shock factor (HSF)1 and thereby inhibiting the expression of Hsps (e.g., Hsp70) or activating the NF-kB pathway through the activation of its protein clients RIP [41] (Figure 1). In view of these results, Hsp60 and Hsp90 modulators appear as potentially useful agents for controlling inflammation in the nervous system [42; 43]. Currently, numerous compounds have been designed to inhibit Hsp90 activity, but few have been developed for Hsp60 [15]. Hsp90 inhibitors have been developed to directly act on the chaperone or on its client proteins. Some inhibitors block the Hsp90 folding activity linked to adenosine triphosphate (ATP)-dependent conformation changes [44], while others inactivate its client proteins via proteasomal degradation [45].