Although the health risks of tobacco smoking are well documented, there is increasing evidence that smokers have a lower incidence of some inflammatory and neurodegenerative diseases. Many of the adverse and beneficial effects of smoking might result from the ability of cigarette smoke to suppress the immune system. Nicotine, which is one of the main constituents of cigarette smoke, suppresses the immune system but might have therapeutic potential as a neuroprotective and anti-inflammatory agent.

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Acute and chronic effects of nicotine on the immune system are usually opposite; acute treatment stimulates while chronic nicotine suppresses immune and inflammatory responses. Nicotine acutely raises intracellular calcium ([Ca2+]i) in T cells, but the mechanism of this response is unclear. Nicotinic acetylcholine receptors (nAChRs) are present on neuronal and non-neuronal cells, but while in neurons, nAChRs are cation channels that participate in neurotransmission; their structure and function in nonexcitable cells are not well-defined. In this communication, we present evidence that T cells express α7-nAChRs that are critical in increasing [Ca2+]i in response to nicotine. Cloning and sequencing of the receptor from human T cells showed a full-length transcript essentially identical to the neuronal α7-nAChR subunit (>99.6% homology). These receptors are up-regulated and tyrosine phosphorylated by treatment with nicotine, anti-TCR Abs, or Con A. Furthermore, knockdown of the α7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca2+ response, but unlike the neuronal receptor, α-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca2+]i in T cells. The nicotine-induced release of Ca2+ from intracellular stores in T cells did not require extracellular Ca2+, but, similar to the TCR-mediated Ca2+ response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3ζ and α7-nAChR coimmunoprecipitated with anti-CD3ζ or anti-α7-nAChR Abs. These results suggest that in T cells, α7-nAChR, despite its close sequence homology with neuronal α7-nAChR, fails to form a ligand-gated Ca2+ channel, and that the nicotine-induced rise in [Ca2+]i in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.

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Rationale: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis.Objectives: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis.Methods: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. Measurements and Main Results:The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82).Conclusions: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.