Stress Facilitates Recovery from Subcutaneous E coli Challenge A Role for eHsp72

We have completed a series of studies that lend support to the hypothesis that stress-induced increases in eHsp72 functions to facilitate innate immunity in the presence of pathogenic challenge (E. coli). First, rats exposed to tailshock stress and challenged with subcutaneous E. coli have an increase in eHsp72 at the site of inflammation (Campisi et al., 2003b). Second, eHsp72 administered to the site of inflammation in the absence of stress improved recovery from bacterial challenge (Campisi et al., 2003b). Third, prazosin in vivo blocked the tailshock-induced increase of eHsp72 in the blood (Johnson et al., 2005), and preliminary data suggests that prozosin also blocks the increase eHsp72 at the inflammatory site and prevented the stress-induced reduction in bacterial load at the inflammatory site. Fourth, in vivo immunoneutralization of eHsp72 by anti-Hsp70-Ab46 at the site of inflammation attenuated the facilitory effect of tailshock stress on bacterial inflammation development and resolution. Importantly, anti-Hsp70-Ab46 (generously provided by Dr. Asea) blocked eHsp72 but not LPS-stimulated NO release from macrophages, tested in vitro. Finally, prelimary data suggest that low doses of LPS + eHsp72 in vitro results in synergistic NO response from macrophages.

4.7. Summary

As depicted in Figure 3.3 and previously discussed (Fleshner and Laudenslager, 2004; Fleshner and Johnson, 2005), we propose that exposure to a stressor activates the sympathetic nervous system leading to the release

Figure 3.3. Depicted is our current hypothesis of how exposure to acute stress can lead to potentiated innate immunity. After exposure to a variety of stressors, the body responds by activating the sympathetic nervous system to release norepi-nephrine. Norepinephrine then binds to alpha1-adrenergic receptor and stimulates the release of extracellular heat shock protein 72 (eHsp72) into the blood. Furthermore, we suggest that in presence of a pathogen and perhaps an inflammatory site, the circulating eHsp72 can extravasate into tissues and interact with innate immune cells to facilitate their responses.

Figure 3.3. Depicted is our current hypothesis of how exposure to acute stress can lead to potentiated innate immunity. After exposure to a variety of stressors, the body responds by activating the sympathetic nervous system to release norepi-nephrine. Norepinephrine then binds to alpha1-adrenergic receptor and stimulates the release of extracellular heat shock protein 72 (eHsp72) into the blood. Furthermore, we suggest that in presence of a pathogen and perhaps an inflammatory site, the circulating eHsp72 can extravasate into tissues and interact with innate immune cells to facilitate their responses.

of eHsp72 into the blood via an a^DR-medicated mechanism. If the animals are challenged with E. coli, eHsp72 extravasates from the blood into the subcutaneous space due to bacterial stimulated release of other inflammatory mediators that render the blood vessel leaky (PGE2, BK, etc.) (Ali et al., 1997). This is supported by recent evidence that the blockade of vascular leaking at the inflammatory cite prevents the local accumulation, but not elevated circulating levels, of eHsp72 after stress (Sharkey et al., 2005). Extracellular Hsp72 at the inflammatory site binds to TLR-2 and TLR-4 on macrophage and/or neutrophils. Macrophages and/or neutrophils that have received a stimulatory signal via CD14 binding to LPS will mount potentiated innate immune responses (i.e., NO,TNF, IL-1, IL-6) that result in optimal bacterial killing. The release of eHsp72 in response to a global stressor such as uncontrollable tailshock, therefore, facilitates innate immune function only in the presence of pathogenic challenge. This is consistent with previous literature on the priming effects of stress on innate immunity (Johnson et al., 2002a, 2002b, 2003b).

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