Figure 2.

Diverse effects of HSPs on inflammation. The exact role of HSPs in the regulation of innate and adaptive immune responses is influenced by several factors. Transcription of HSP genes is regulated by HSF1, which normally presents in the cytosol in its inactive form bounded to HSPs. Under stress conditions, the monomeric HSF1 dissociates from HSPA/C, trimerizes, and subsequently translocates to the nucleus, where it upregulates the expression of HSPs. Moreover, HSF1 was suggested to have bi-directional effect on the expression of inflammatory factors. HSF1 was shown to inhibit the expression of TNF-α by binding to its promoter, while it was also able to activate TNF-α as part of a multiprotein complex. Similarly, HSF1 was found to bind directly to IL-6 promoter opening of the chromatin structure thereby facilitating the access of activator or repressor molecules. The newly synthesized intracellular HSPs have protective and anti-apoptotic effects. Both HSPB1 and HSPA1 were shown to inhibit the activation of NF-κB by inhibiting IKK, thereby exerting an anti-inflammatory function. At the same time, cellular stress promotes the release of HSPs into the extracellular space. Lethal stress leads to the passive secretion of HSPs from necrotic cells, which usually induce a strong pro-inflammatory activity. On the other hand, HSPs can be secreted actively even under non-lethal, mild stress conditions. Although the classical protein secretory pathways are not secreting HSPs, alternative secretory mechanisms, such as exosomal release can be the basis of their regulated export. HSPs were found in the lumen of exosomal vesicles or they can occur in a membrane-associated form. Luminal HSPs cannot interact directly with the target cells only if the vesicles “burst” outside of the cell or fuse with the cell membrane, releasing HSPs into the extracellular space or into the cytosol. HSPs presented in the membrane of extracellular vesicles can bind to various surface receptors, such as toll-like receptors, that can induce the NF-κB pathway. Moreover, by sequestering antigenic molecules, HSPs are involved in antigen presentation. On the other hand, many studies confirmed that exogenous HSPA1 and HSPB1 exert anti-inflammatory effects through yet undefined mechanism in different pathological conditions. (Reviewed in van Noort, 2008; De Maio and Vazquez, 2013; Kim and Yenari, 2013). Red arrows denote pro-inflammatory, while blue arrows denote anti- inflammatory processes.