Peripheral Sympathetic Denervation Alters Both the Primary and Memory Cellular Immune Responses to Herpes simplex Virus Infection

Abstract

Numerous studies have sought to delineate the impact of neuroendocrine function on overall immune responsiveness. Using various murine models, we and others have previously shown that both adrenal-dependent and adrenal-independent mechanisms associated with psychological stress modulate components of both the primary and memory cellular immune responses to herpes simplex virus type 1 (HSV-1) infection. We have extended these studies by determining the impact of 6-hydroxydopamine (6-OHDA)-mediated peripheral sympathetic denervation on both responses. C57BL/6 mice treated with 6-OHDA (200 mg/kg) exhibited reduced generation of both primary lymph node- and splenic-derived cytotoxic T lymphocytes (CTL) following a local (footpad) and systemic HSV infection, respectively. 6-OHDA also suppressed activation of HSV-specific memory CTL (CTLm). In both models, alterations in cytokine production and lymphocyte subset distribution were also observed. Administration of 6-OHDA also resulted in substantial but transient activation of the hypothalamic-pituitary-adrenal (HPA) axis as was indicated by a dramatic elevation of serum corticosterone and hypothalamic Fos expression. Moreover, the corticosterone levels were directly correlated with the extent of CTLm activation. Together, these findings suggest that peripheral sympathetic denervation alters immune function through activation of the HPA axis.

Sympathetic nervous system control of anti-influenza CD8+T cell responses

“…In contrast to our findings, Bonneau and colleagues (25) reported that 6-OHDA decreases T CD8ϩ responses to i.p. infections with herpes simplex virus (HSV).…”

“…infections with herpes simplex virus (HSV). This discrepancy could be explained by numerous differences between the studies, particularly the timing of 6-OHDA treatment, because Bonneau ablated the SNS 24 h after viral infection (25). Because 6-OHDA treatment can greatly modify innate immune responses (13,16), this could contribute to the differences between our findings and those of Bonneau and colleagues (25).…”

“…This discrepancy could be explained by numerous differences between the studies, particularly the timing of 6-OHDA treatment, because Bonneau ablated the SNS 24 h after viral infection (25). Because 6-OHDA treatment can greatly modify innate immune responses (13,16), this could contribute to the differences between our findings and those of Bonneau and colleagues (25). Using a different HSV model system in mice, Carr and colleagues (26) reported that 6-OHDA treatment before ocular infection does not significantly modify T CD8ϩ responses in draining lymph nodes.…”

“…As described by van Endert and colleagues (23), peptide determinants are rapidly liberated from the fusion protein by Ub-hydrolases and behave like cytosolic minigene products. 6-OHDA treatment increased the primary T CD8ϩ response to Ova 257-264 and to the immunodominant VV determinant B8R [20][21][22][23][24][25][26][27] (Fig. 2B).…”

Chemical sympathectomy increases susceptibility to ocular herpes simplex virus type 1 infection

“…The importance of innervated immune organs is underscored by findings that suggest disruption of noradrenergic fibers using the neurotoxin, 6-hydroxydopamine (6OHDA) results in changes in antibody production (Livnat et al, 1985;Kohm and Sanders, 1999), delayed-type hypersensitivity responses (Madden et al, 1989), natural killer (NK) cell activity (Reder et al, 1989), and T cell proliferation (Moynihan et al, 2004) which collectively, can modify host susceptibility to infection (Leo et al, 1998;Miura et al, 2001) and severity of autoimmune disease including experimental autoimmune encephalitis (Chelmicka-Schorr et al, 1988) and experimental rheumatoid arthritis (Felton et al, 1992;Härle et al, 2005). 6OHDA treatment results in the activation of the hypothalamic pituitary adrenal axis leading to an elevation in circulating corticosterone (Leo et al, 1998), a potent immunomodulator (McEwen et al, 1997). Likewise, 6OHDA treatment in adult rodents results in the reversible destruction of noradrenergic termini through a loss in membrane integrity elicited by the production of hydrogen peroxide and hydroxyl radicals (Picklo, 1997).…”