SIV infection decreases sympathetic innervation of primate lymph nodes: The role of neurotrophins

Abstract

The sympathetic nervous system regulates immune responses in part through direct innervation of lymphoid organs. Recent data indicate that viral infections can alter the structure of lymph node innervation. To determine the molecular mechanisms underlying sympathetic denervation during Simian Immunodeficiency Virus (SIV) infection, we assessed the expression of neurotrophic factors and neuromodulatory cytokines within lymph nodes from experimentally infected rhesus macaques. Transcription of nerve growth factor (NGF), brain derived neurotropic factor (BDNF) and neurotrophin-4 (NT4) decreased significantly in vivo during chronic SIV infection, whereas expression of the neuro-inhibitory cytokine interferon-γ (IFNγ) was up-regulated. Acute SIV infection of macaque leukocytes in vitro induced similar changes in the expression of neurotrophic and neuro-inhibitory factors, indicative of an innate immune response. Statistical mediation analyses of data from in vivo lymph node gene expression suggested that coordinated changes in expression of multiple neuromodulatory factors may contribute to SIV-induced depletion of catecholaminergic varicosities within lymphoid tissue. Given previous evidence that lymph node catecholaminergic varicosities can enhance SIV replication in vivo, these results are consistent with the hypothesis that reduced expression of neurotrophic factors during infection could constitute a neurobiological component of the innate immune response to viral infection.

Autonomic Neuropathy in HIV is Unrecognized and Associated with Medical Morbidity

“…17 Others have shown a complicated interaction between the sympathetic innervation of lymph nodes and viral replication, with an overall decrease in sympathetic innervation of lymph nodes in the rhesus macaque following SIV infection, but enhanced viral replication adjacent to the remaining sympathetic varicosities. 18,19 This study has limitations. The data are cross-sectional, so a determination of whether there is a causal relationship between autonomic neuropathy and morbidity cannot be made, and actual (as opposed to predicted) mortality rates cannot be known.…”

Stress-induced remodeling of lymphoid innervation

“…However, it is conceivable that other neurotrophic factors known to regulate sympathetic innervation might also participate (e.g., NT3 or BDNF, both of which have been detected in our studies of lymph node gene expression) Sloan, Capitanio et al 2007b;Sloan, Nguyen et al 2007). Demonstration of a causal role for NGF will require direct molecular manipulations (e.g., via anti-NGF neutralizing antibodies or analysis of receptor knock-out animals).…”

“…As noted above, analysis of macaque peripheral blood mononuclear cells suggest that lymphocytes are not the primary contributor (< 10% of total lymph node NGF transcription), and catecholamines do not substantially up-regulate NGF expression by leukocytes (Sloan, Capitanio et al 2007b;Sloan, Capitanio et al 2007a;Sloan, Cox et al 2007;Sloan, Nguyen et al 2007). Perhaps sympathetic varicosities are themselves the major NGF releasers in the lymph node (Zafra, Hengerer et al 1990;Hasan, Pedchenko et al 2003)?…”

“…However, lymphotrophic viral infections can denervate lymphoid tissues (Kelley, Moynihan et al 2003), and similar effects have been observed in the context of SIV infection (Sloan, Nguyen et al 2007). These dynamics raise the possibility that localized inflammatory signaling might contribute to the dynamic equilibrium of sympathetic innervation.…”

“…Which neurotrophins are responsible?-Current results suggest a strong relationship between NGF up-regulation and stress-induced arborization of sympathetic innervation in lymphoid tissue (Carlson, Albers et al 1995;Sloan, Tarara et al 2006;Sloan, Capitanio et al 2007b;Sloan, Nguyen et al 2007). However, it is conceivable that other neurotrophic factors known to regulate sympathetic innervation might also participate (e.g., NT3 or BDNF, both of which have been detected in our studies of lymph node gene expression) Sloan, Capitanio et al 2007b;Sloan, Nguyen et al 2007).…”