A Sino-U.S. collaborative study has demonstrated that acupuncture regulates inflammation by activating pro- or anti-inflammatory signaling pathways, while mitigating cytokine storms in mice with systemic inflammation, the study authors reported in the Aug. 12, 2020, edition of Neuron.

The study also found that the acupuncture site, intensity and timing determined how it affected response, which has important implications for acupuncture use in inflammatory diseases and as adjunctive cancer therapy.

Acupuncture was further shown to influence how mice coped with the aberrant immune system reaction of cytokine storm due to rapid excessive release of pro-inflammatory cytokines.

Our study provides an insight into how acupuncture can drive distinct autonomic pathways and modulate inflammation in acupoint-, stimulation intensity- and disease state-dependent manners, said study leader Qiufu Ma, a professor in the Dana Farber Cancer Institute and the Department of Neurobiology at Harvard Medical School.

Cytokine storms are a characteristic of inflammatory diseases, notably bacterial or viral infections causing sepsis, an organ-damaging, often-fatal inflammatory response.

Cytokine storms can also be caused by excessive inflammatory responses to traumatic tissue injury, some surgeries, and cancer immunotherapies such as immune checkpoint inhibition, but currently there are no FDA-approved treatments for severe cytokine storms, noted Ma.

For cancer patients receiving immunotherapy who develop inflammatory side effects, milder symptoms might be relieved by corticosteroids, which have their own side effects, he said.

In COVID-19 patients, early pilot studies have suggested using an antibody against the cytokine, interleukin-6 (IL-6), but larger clinical trials are needed to confirm the efficacy and safety of this approach, he told BioWorld.

A traditional Chinese medicine technique, acupuncture has become increasingly integrated into Western medicine, particularly for treating chronic pain and gastrointestinal disorders.

It involves mechanical stimulation of acupoints, supposedly triggering nerve signaling and affecting the function of internal organs corresponding to those acupoints, but acupunctures basic underlying mechanisms have not been fully elucidated.

In their new study, Ma and his research team investigated the use of electroacupuncture stimulation (ES), in which ultra-thin electrodes offer better control of stimulation intensity than traditional needles.

The researchers investigated two cell types secreting the neurotransmitters known to be important inflammatory mediators: adrenal gland chromaffin cells, the main producers of adrenaline, noradrenaline (NA) and dopamine, and peripheral NA neurons.

To determine the precise role these cells play in inflammatory responses, the researchers used a novel genetic tool to ablate chromaffin cells or NA neurons.

We genetically introduced the human diphtheria toxin receptor (DTR) selectively to molecularly defined sympathetic cells, such as those marked by expression of neuropeptide Y (NPY), explained Ma.

Injecting a modified diphtheria toxin that does not cross the brain-blood barrier can selectively ablate DTR-expressing cells, creating mice lacking both NPY-expressing chromaffin cells and NA neurons, or those with a more selective ablation of NPY-expressing chromaffin cells via injecting low-dose toxin only into the adrenal gland.

That allowed inflammatory response comparison in mice with and without those cells, to determine their role in modulating inflammation. The markedly different responses then identified those cells as key regulators of inflammation.

Hind-limb administration of low-intensity ES to mice with a bacterial toxin-induced cytokine storm was shown to activate the vagus-adrenal axis, inducing dopamine secretion from chromaffin cells.

We used the induction of a neuronal activation marker to show that low-intensity ES activated hind-brain vagal efferent neurons, which are known to innervate thoracic and visceral organs and tissues, said Ma.

We then showed that low-intensity ES could reduce cytokine storms and promote survival, and that these ES effects were lost in mice with transected vagal efferents or in those with ablation of NPY-expressing adrenal chromaffin cells, suggesting involvement of the vagal-adrenal anti-inflammatory axis.

Specifically, treated animals had more than 50% reductions in the cytokines, tumor necrosis factor-alpha (TNF-a), IL-6 and IL-1b, than untreated controls, and prolonged survival rates of 60% vs. 20%, respectively.

In addition, the vagus-adrenal axis was shown to be activated by hind-limb ES, but not by that using abdominal acupoints, demonstrating the importance of acupoint selectivity in driving specific anti-inflammatory pathways.

Treatment timing was also found to be critical, with high-intensity abdominal stimulation producing markedly different outcomes, depending on when treatment occurred.

For example, animals treated before developing cytokine storm had lower levels of inflammation during subsequent disease and their survival increased from a range of 20% to 30% to a range of 70% to 80%.

Conversely, those treated after disease onset and during the cytokine storm peak experienced worse inflammation and more severe disease.

Together, those findings suggest that ES could be a versatile treatment modality, from adjunct therapy for sepsis to targeted treatment of site-specific inflammation, such as in inflammatory intestinal diseases.

Acupuncture might also help modulate inflammation due to cancer immune therapy, which can trigger cytokine storms, and is currently used in integrative cancer treatment to help patients tolerate treatment side effects.

However, before considering any therapeutic use, those findings must be further confirmed in animals and humans, optimal ES parameters must be defined and its safety established.

Safety

High-intensity ES can drive spinal-splenic noradrenergic sympathetic neuronal pathway, potently reducing inflammation if performed before cytokine storm induction, said Ma.

However, after the first cytokine storm wave has peaked, high-intensity ES can exacerbate inflammation and increase fatality rates, due to altered NA receptor profiles in immune cells switching from anti-inflammatory to pro-inflammatory dominance.

As such, high intensity ES may be associated with unforeseen safety issues, but fortunately low intensity ES is sufficient to drive the vagal-adrenal axis and safely attenuate inflammation in a disease state-independent manner, Ma said.

In the future, he said, inflammation modulation needs to be fine-tuned, since excessive suppression could reduce the ability of the immune system to fight with infection, necessitating future human studies to optimize stimulation parameters.

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