Cutting edge: Sympathetic nervous system increases proinflammatory cytokines and exacerbates influenza A virus pathogenesis

Abstract

Although the sympathetic nervous system innervates the lung, little is known about its participation in host immunity to pulmonary pathogens. In this study, we show that peripheral sympathectomy reduces mouse morbidity and mortality from influenza A virus-induced pneumonia due to reduced inflammatory influx of monocytes, neutrophils, and NK cells. Mortality was also delayed by treating mice with an alpha-adrenergic antagonist. Sympathectomy diminished the immediate innate cytokine responses, particularly IL-1, which was profoundly reduced. These findings demonstrate an unexpected role for the sympathetic nervous system in innate antiviral immunity and in exacerbating the pathology of a virus of great significance to human and animal health.

Figures

FIGURE 1

6-OHDA treatment increases survival to lethal IAV infection. 6-OHDA or control mice (15 per group) were infected with 1 LD50 PR8 i.n. Solid gray lines: 6-OHDA treated PR8 infected. Solid black lines: control PR8 infected. Dashed gray line: 6-OHDA mock infected. Dashed black line: control mock infected. Left, Survival. Right, Weight loss. This experiment was repeated 10 times with similar results.

FIGURE 2

6-OHDA treatment reduces IAV-induced histopathology. A–D, Lower magnification (original magnification ×25) view of mouse lungs stained by H&E [representative blood vessels (V) and bronchi (B) are labeled]. Uninfected mouse lung without (A) or with (B) treatment demonstrate normal pulmonary histology. Five days postinfection with PR8 with saline (C) or with 6-OHDA treatment (D; bronchitis, bronchilolitis, and alveolitis were present in both groups, but decreased by 6-OHDA treatment). High magnification view (original magnification ×400) of lungs from saline (E) or 6-OHDA (F) treatment groups. Greater numbers of lymphocytes, neutrophils, and macrophages were present in the saline group compared with the 6-OHDA–treated group, which maintained better aeration. This experiment was repeated twice with similar results.

FIGURE 3

6-OHDA treatment reduces IAV-induced cellular infiltrates into lung parenchyma and BAL. 6-OHDA–treated or control mice were infected with 1 LD50 PR8 i.n. and cellular infiltrates quantified 5 d postinfection. Gray bars represent control group, and black bars represent 6-OHDA–treated group. Right graph shows infiltrate into lung parenchyma, and left graph shows infiltrate into BAL. This experiment was repeated twice with similar results. *p < 0.05; **p < 0.005.

FIGURE 4

6-OHDA treatment reduces IAV-induced cytokine and chemokine production in BAL. 6-OHDA–treated or control mice were infected with 1 LD50 PR8 i.n., and cytokines and chemokines were measured in BAL days 0, 1, 2, 3, 4, 6, and 8 postinfection. Solid lines represent control mice, and dashed lines represent 6-OHDA–treated mice. This experiment was repeated twice with similar results.

FIGURE 5

α, but not β, antagonists improve survival following lethal IAV infection. Mice (10 per group) were infected with 1 LD50 PR8 i.n. and monitored for survival. Right graph: mice were treated with nadolol (β-blocker) or saline. Left graph: mice were treated with phentolamine (α-blocker) or saline. This experiment was repeated with similar results.