Sympathetic excitotoxicity in sepsis: Pro-inflammatory priming of macrophages by norepinephrine

Michael Miksa, Rongqian Wu, Mian Zhou, Ping Wang

Research output: Contribution to journalReview articlepeer-review

62 Scopus citations


In the history of medicine, the interaction between mind and body has been repeatedly proposed. However, the influence of the nervous system on the immune regulation has, until now, drawn little attention. In this regard, the adrenergic system has been explored, and mainly catecholamine-mediated anti-inflammatory effects have been described. These inhibitory effects of epinephrine and norepinephrine were found to be mediated by beta 2-adrenoceptors expressed on mononuclear cells. Recently, the role of the parasympathetic nervous system in the local anti-inflammatory reflex has been investigated. Stimulation of the vagus nerve decreases the proinflammatory response of macrophages via alpha7-cholinergic receptors. Thus, both the sympathetic and parasympathetic nervous systems are thought to work hand in hand in their anti-inflammatory responses. Here we discuss the deteriorating effects of the release of norepinephrine in sepsis. We have discovered that organ dysfunction in severe sepsis is mediated at least in part by an increase in pro-inflammatory cytokine release from Kupffer cells, which is caused by a priming via gut-derived norepinephrine. The sympathetic nervous system and gut-derived norepinephrine mediate the pro-inflammatory effects by activating alpha2A-adrenoceptor on Kupffer cells. In this review, we will focus on the differential function of the noradrenergic system on local and systemic inflammatory responses and the possibilities of the modulation of sympathetic outflow by centrally active inhibitors such as the novel peptide ghrelin or NMDA-receptor blockers. Furthermore, we will introduce the new concept of "sympathetic excitotoxicity in sepsis" characterized by the neurogenic priming of the systemic pro-inflammatory response. "The brain and the nerves are the true body of our Ego; the remainder is just the body of that body, the nourishing and protecting bark of the delicate core." (Jean Paul, a German philosopher of the European Enlightenment period, 1763-1825).

Original languageEnglish (US)
Pages (from-to)2217-2229
Number of pages13
JournalFrontiers in Bioscience
Issue numberSUPPL. 1
StatePublished - 2005
Externally publishedYes


  • Alpha-Adrenoceptor
  • Ghrelin
  • Inflammation
  • Kupffer cells
  • Macrophages
  • Norepinephrine
  • Review
  • Sepsis
  • Sympathetic Nervous System

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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