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Macrophages release inflammatory signals (TNF, IL-1, IL-6, IL-18) that result in tissue inflammation. Nicotine is anti-inflammatory by acting on the acetylcholine receptors normally responsive to acetylcholine released by the vagus nerve. Acupuncture is anti-inflammatory by stimulating the vagus nerve-mediated effects on macrophages.

The relationship between the nervous and immune systems has been accepted as a reality, but has been elusive. Numerous examples in alternative medicine appear to show that a variety of treatments have immunological impacts, but explanations based on cellular biology have been slow to materialize. Here I will discuss some of the recent experiments that reveal obvious connections between nerves and macrophages that may explain in medical terms at least part of the efficacy of acupuncture.

Dilation of blood vessels that causes reddening, swelling and warmth of tissue inflammation results from changes at the cellular level. If the sentinel cells of a tissue, macrophages, are exposed to a bacterium, for example, receptors on the surface of the macrophages bind fragments of the bacterial cell wall, i.e. lipopolysaccharide (LPS) or endotoxin, and signal the expression of five dozen genes. Among these genes are inflammatory mediators, TNF, IL-1, IL-6, IL-18, that are released from the macrophages and trigger behavioral changes in the surrounding cells of the tissue, which are observed as inflammation.

Expression of the inflammatory genes is controlled by a master transcription factor, NFkB. Thus, LPS will signal a macrophage, NFkB is activated, inflammatory genes are expressed, mediators are secreted and tissue inflammation is observed. Dozens of different inputs determine if NFkB will be activated or quieted. Nicotine for example has been observed to block inflammation by LPS.

It has been shown that macrophages also have receptors for the neurotransmitter acetylcholine that is released by branches of the vagus nerve in the intestines. It has also been recently shown that excitation of the vagus nerve releases acetylcholine and blocks the response of intestinal macrophages to LPS. Thus, vagus stimulation is anti-inflammatory and blocks NFkB activation through a competing transcription factor, STAT3. Nicotine acts by binding to the acetylcholine receptors of the macrophages and is similarly anti-inflammatory.

Acupuncture appears to work by needle stimulation of the vagus nerve that sends signals to the brain. Returning nerve impulses via the vagus nerve subsequently release acetylcholine back into the surrounding tissue and block inflammation. In this context, acupuncture would be exploiting an existing inflammation dampening system, that would serve to localize spreading inflammatory signaling and emphasize the source of inflammation for action by the circulating elements of the immune system.

Inflammatory Mast Cells Silenced

In a previous article, I outlined the role of the vagus nerve in responding to infection/damage signals by producing signals that inhibit inflammation. In a recent article (ref. below), the role of the vagus nerve in gut inflammation was examined using real-time biophotonic labeling. Basically that means that a video camera sensitive to infrared can be used to detect infrared dyes produced when NFkB is activated -- the camera is able to visualize regions of inflammation in living mice. Using this technique, researchers were able to demonstrate that cutting the vagus nerve produced heightened inflammation in gut treated with an irritant. The vagus nerve appears to stimulate regulatory T cells that lower the activity of inflammatory cells.

Inflammation/NFkB Activation Visualized in Live Mice

The studies were performed in a mouse line constructed to express an infrared fluorescent protein in cells in which the inflammation transcription factor, NFkB, is activated. Mice of this strain were prepared with and without the vagus nerve intact leading to the intestines. The mice were then exposed to sodium dextran sulfate (DSS) to simulate inflammatory bowel disease symptoms.

Cutting the Vagus Nerve Permits Inflammation

Mice with intact vagus nerves exhibited much less inflammation in their gut than those without vagus innervation. The cut vagus experiments demonstrated that the vagus nerve was responsible for suppressing inflammation. Further experiments were performed to determine if the inflammatory and anti-inflammatory reactions could be transferred to other mice by transferring cells from the treated mice.

Regulatory T Cells (CD4+, CD25+) Block Inflammation

Transfer experiments showed that inflammatory T cells (CD4+, CD25-) from cut vagus, DSS mice would cause bowel inflammation in other mice, but that did not happen with the same type of cells from mice with intact vagus nerves. Further tests showed that either cutting the vagus or adding inflammatory T cells from a mouse with a cut vagus, reduced the population of regulatory T cells (CD4+, CD25+) in control mice treated with DSS. So, without the vagus stimulation, the regulatory T cell population declined in the presence of inflammatory signals.

Absence of Regulatory T Cells Can Explain Many Inflammatory Diseases

In many inflammatory diseases, e.g. celiac, Crohn’s disease, rosacea, there appears to be a deficiency of regulatory T cells. In the absence regulatory T cells, signals from vagus nerves will no longer produce anti-inflammatory suppression. In fact the same nerve signals may become inflammatory. This would explain why rosaceans will become inflamed by hot or cold stimulation that would normally lead to anti-inflammatory stimulation of regulatory T cells. Similarly, capsaicin, castor oil and menthol, which normally produce an anti-inflammatory response, produce inflammation in rosaceans.

[Vagal stimulation exercise links:  here and here.]

reference:
OMahony C, van der Kleij HP, Bienenstock J, Shanahan F, OMahony L. 2009. Loss of vagal anti-inflammatory effect - in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. Aug 12. [Epub ahead of print]