## 2 Immunomodulatory Function of Extracellular Hsp60, Hsp70, and Hsp90
For example, geldanamycin induces the degradation of Hsp90 client proteins of the RIP family with the consequent inhibition of TNF-mediated IkB kinase and NF-kB activation [41]. Furthermore, Hsp90 forms a complex with HSF1, blocking its translocation to the nucleus and, thereby, impedes the upregulation of Hsp70 and other anti-inflammatory molecules [46] (Figure 1). Most of the compounds that inhibit Hsp70 function by targeting its ATP hydrolysis activity or specific cysteine residues [47]. Extracellular Hsp60, Hsp70, and Hsp90 in Acute Nervous System Injury and Chronic Neurodegenerative Diseases  
Neurodegenerative diseases are accompanied by inflammatory responses aimed at eliminating dead and damaged neuronal cells to restore the compromised area to its normal status [7]. It should be borne in mind that while short-lived inflammatory responses generally have a beneficial effect, excessive and persistent release of inflammatory mediators can be harmful to brain tissue [9]. Moreover, prolonged activation of microglia and astrocytes could also lead to the alteration of their beneficial functions, which they display under normal conditions [48]. Therefore, it is not surprising that neuroinflammation contributes to CNS diseases [49]. Although different in their origins, many neurodegenerative conditions are characterized by shared cellular responses that promote the upregulation of molecular chaperones as the first line of defense against misfolded, dysfunctional, and aggregation-prone proteins [50]. There is increasing evidence for the release of Hsp60, Hsp70, and Hsp90 into the extracellular environment, with functions that are complementary or independent of those of their intracellular counterparts. Since these chaperones lack a secretion signal in their sequences, the mechanisms by which they are released are poorly understood. In vitro and in vivo studies with Hsp60 have unveiled secretion pathways, involving lipid rafts and exosomes, which would explain the presence of Hsp60 in extramitochondrial sites such as interstitial space, cellular membrane, and biological fluids [51]. Similarly, nontraditional secretion mechanisms participate in the membrane delivery and release of Hsp70, involving lipid rafts [52] and lysosomes [53], in line with its role as a lysosomal stabilizer [54]. Secretion of Hsp90 via exosomes depends on its ATPase function and on the open or closed conformational state of the Hsp90 dimer: the open state promotes Hsp90 release via exosomes, whereas the closed state blocks this process [55]. Different types of CNS cells, including neurons and glial cells, can release exosomes with their cargo of specific molecules that could affect the function of acceptor cells [56]. At the extracellular level, Hsp60 is known to contribute to neuroinflammationflammation with possible negative implications: this chaperone is highly expressed in activated microglia, and when released extracellularly, it induces neuroinflammation with neuronal cell death [57]. For this reason, inhibition of Hsp60 expression and its release represents a possible therapeutic mechanism applicable to neurodegenerative diseases. The pro- and anti-inflammatory effects of extracellular Hsp60, Hsp70, and Hsp90 in AD, PD, ALS, HD, and MS are summarized in Table 1 and discussed in the following paragraphs.