This post is an edited version of two articles from Harvard Magazine indicated below. Please use the links below to view the full articles for a more complete discussion.
How Acupuncture Relieves Inflammation by Debra Bradley Ruder January-February 2021
Harvard Magazine https://harvardmagazine.com/2021/01/right-now-acupuncture-relieves-inflammation states: "In Inflammation can both heal and harm. A core component of the immune system, it’s essential for recovering from an injury or infection—but too much can contribute to diabetes, heart disease, arthritis, cancer, and other serious illnesses.
“You need to fine-tune inflammation,” says professor of neurobiology Qiufu Ma, of Harvard Medical School and Dana-Farber Cancer Institute. He and a team of HMS neuroscientists, joined by collaborators in Houston and China, recently demonstrated one way to do that—with acupuncture.
During animal experiments, the researchers found that acupuncture activates different nerve pathways that can either suppress or promote inflammation, depending on where, when, and how it is used. Their work revealed that acupuncture stimulation can reduce systemic inflammation in mice experiencing cytokine storm, an extreme immune response in which the body rapidly releases excess inflammatory proteins. (Such dangerous and sometimes deadly inflammation is a hallmark of sepsis and has been seen with COVID-19}.
But Ma’s team also discovered that acupuncture can worsen inflammation when administered at the wrong time, suggesting the ancient healing technique can be harmful if not practiced properly. These findings, described in the journal Neuron in August, hold promise for improving acupuncture’s safety and effectiveness and eventually may help treat patients with inflammatory diseases.
For Ma, these collective findings signal that the 3,000-year-old practice of acupuncture—far from being folk medicine—has a scientific basis that could eventually be understood. That’s a puzzle he hopes to investigate further, through basic research in animals and work with clinical partners to examine how acupuncture treatments might help humans better “fine-tune” inflammation."
According to another article in the Harvard magazine entitled Raw and Red-Hot: Could inflammation be the cause of myriad chronic conditions? by Jonathan Shaw May-June 2019 https://harvardmagazine.com/2019/05/inflammation-disease-diet "By analyzing biomarkers in the blood of 27,055 women participating in a long-term study" ... “reduced inflammation was the biggest explainer, the biggest contributor to the benefit of activity,” says Mora, “because we hadn’t hypothesized that. We knew that regular exercise does reduce inflammation over the long term, but we also knew that acute exercise transiently increases inflammatory biomarkers during and immediately after exertion.” About a third of the benefit of regular exercise, they found, is attributable to reduced inflammation.
The anti-inflammatory effect of exercise was much greater than most people had expected. That raised another question: whether inflammation might also play a dominant role in other lifestyle illnesses that have been linked to cardiovascular disease, such as diabetes and dementia.”
“large-scale human clinical trial to dispel any lingering doubt: the immune system’s inflammatory response is killing people by degrees.”
“Today, inflammation is a focus of intense research in many fields. Roni Nowarski, assistant professor of neurology and immunology, explains that inflammation is important across a range of seemingly distinct pathologies because immune cells are everywhere, even resident in organs, where they play an important role in monitoring and maintaining health. The paradigm that everyone knows—that the immune system’s front line consists of circulating white blood cells that patrol the body to guard against infection and injury—is a bit misleading. An important arm of the immune system resides outside the blood vessels. Pac-Man-like macrophages occupy tissues, where they engulf and digest invading pathogens, debris, and dying cells. An invaluable role of these tissue macrophages is to “act as sensors,” Nowarski says. “They have hard-wired mechanisms to detect signals that are out of the ordinary,” and so play a critical role in maintaining a healthy equilibrium. “If there is any fluctuation,” he notes, “the role of these cells is to return the system to this point of homeostasis.”
These tissue-based white blood cells can also call for backup. When that happens, the heavy guns of the immune system, neutrophils, are first to arrive on the scene. These are “potent, aggressive cells” that can kill infectious agents, Nowarski explains, but “can also cause a lot of damage to healthy tissue.” That’s why most neutrophils are short-lived, with a tightly regulated lifespan of just a few hours: unchecked, they would cause serious harm. Neutrophils, which originate in bone marrow, also play a role in relaxing the endothelial barrier that separates blood from tissue, so immune cells can cross that barrier to reach the site of attack. Other signals—like the IL-1beta protein that Libby and Ridker blocked in their trial—promote adhesion, in order to capture circulating immune cells that reach the damaged tissue. This stickiness, though desirable in the short term, is also the basis of the process that can lead to atherosclerosis if it continues indefinitely. The endgame of a healthy immune response, on the other hand, involves cleanup, says Nowarski: even the death and uptake of neutrophils as they are gobbled by macrophages serve as signals to resolve inflammation.
Why inflammation sometimes doesn’t resolve, and becomes chronic instead, is in some sense easily explained in evolutionary terms. “If I’m living 70,000 years ago at a time of food shortage,” says Ridker, “and there’s a drought, the 5 to 10 percent of people who will survive that drought are likely to have insulin resistance”—a tendency to store more calories as fat. “They’re going to live a little longer,” he continues. “When it finally rains, food comes, and that’s the survivor group. In a modern world of too much food, [insulin resistance] leads to diabetes. But in prehistory, it’s terribly important for survival.” While stored fat is beneficial during times of famine, it also harbors potentially damaging pro-inflammatory signaling molecules (see “Eating to Excess: Metabolic Inflammation,”).
A second evolved factor is that prior to the development of antibiotics, disease “wiped out half the population before age five. So, people were under evolutionary pressure to have a hyperactive immune system.” Now, “most everybody survives childhood infections,” thanks in large part to vaccines. “But this hyperactive immune system remains, and adversely affects aging.”
“The third piece—beyond starvation and infection—is trauma,” Ridker says. “The saber-toothed tiger—or for women, bleeding to death during childbirth—selects on a genetic basis for hypercoagulable blood. So here we are, by definition all of us lucky enough to be alive today, with a consistent ancestry all the way back to the beginning. And we have all inherited a pro-inflammatory, insulin resistant, pro-coagulable state. Under the circumstances,” he continues, the fact that “we have an epidemic of diabetes and heart disease makes complete sense.” Evolutionary pressures have shaped a physiological system which is phenomenally well suited for surviving childhood infection, starvation, and predation. “But it contributes to many disorders of chronic aging, because from an evolutionary perspective, if you’ve had your kids, you’re kind of done.”
Evolution also explains why the underlying biology appears so similar from one disease to the next.”
“Chronic inflammation is uniformly damaging and is absolutely causal to the process, because if you interfere with it, you can reverse the pathology.” And this ability to control such diseases simply by reversing inflammation is a biological response, dating far back to the time of a common ancestor, that has been retained across diverse species of animals to the present day, he says, pointing to experimental evidence: “If you can make Drosophila [fruit fly] diabetic, and then block the inflammatory response systems, you can cure diabetes in Drosophila, the same way you can reverse it in the mouse, in primates, and in humans, provided that you do it with the right tools. Of course, the higher the organism, the more complex these pathways are, so it takes more effort to define the precise mechanisms to manipulate.”
“the “immune response is enormously expensive, energy-wise.” The intimate relationship between the metabolic and immune systems, he believes, has been maintained because it takes “tremendous energy to mount an effective immune response. While this link is essential to maintain health and homeostasis, abnormalities that develop over time, as in the case of obesity, carry a great risk of damage.””
The metabolic stress that is a hallmark of modern life, the stress that the body has not evolved to handle, is constant eating, he continues. When people eat, energy and nutrients enter the body rapidly, are processed, produce in turn a lot of by-products, and then need to be reduced to “functional substances that are distributed throughout the body, and then disappear very quickly. Many cells and tissues actually undergo a huge amount of stress during this process,” he explains, “as they store appropriate nutrients and dispose of harmful intermediates.” Part of this process also involves mounting an immune response. “The pancreas, for example, must secrete four to five hundred milliliters of enzymes every day” to be able to manage the incoming energy load with every meal. “If you place these organs under constant stress, they start malfunctioning.” The consequence is that “right now, one out of every 10 individuals has diabetes. One out of every four individuals has fatty liver disease. And if you reach a certain age, one out of every three individuals will develop neurodegenerative disease.”
The metabolic stress that underlies these conditions comes from the daily imbalance between how much energy people consume and how much they need, and can process in a healthy manner. The long-term consequence of overconsumption, combined with lack of sufficient expenditure, is stored energy—the accumulation of fat. Excess body fat, especially in the wrong places, is an additional risk factor for inflammation.
Clinical studies implicating stored fat as a source of inflammation have been buttressed by basic research that shows that adipose tissue—body fat—is laced with immune cells, which become more abundant with weight gain, perhaps because fat cells can secrete alarm signals that summon white blood cells. “A fat cell is almost like a primitive immune cell,” says Hotamisligil. “It can request the assistance of immune cells when in trouble, but if the stress continues, and the immune cells remain, they start changing their character and behavior from helpful to harmful.”
A fat cell, or adipocyte, is more than 90 percent triglyceride. If the thin cell wall enclosing this droplet of fat ruptures, an inflammatory response ensues.
And there is additional evidence that the physical structure of fat cells, or adipocytes, which have been described by Stephen O’Rahilly of the University of Cambridge as resembling a fried egg atop a beach ball of fat—with a tiny rim of cytoplasm encircling the droplet of triglyceride—puts them at risk of rupture. Adipocytes are “cells at the edge under the best of circumstances,” explains Hotamisligil. Ninety percent or more of a fat cell’s volume is triglyceride, a substance chemically similar to diesel fuel. The remaining 10 percent is all the space it has for the organelles that perform the normal functions of cell biology. This bloated cell is thus vulnerable to stress, even to the point of bursting and death. When overloaded with stored lipid, fat cells begin to lose their functional and structural integrity and may start spilling their toxic cargo. When cells fail like this, the immune system kicks in, initially to assist in clean-up. Macrophages engorge themselves on the leaking fuel, and may die themselves during this process. But in the long run, what is meant to be a mutually beneficial interaction between the metabolic and immune systems turns into a very dangerous and harmful relationship. Obese individuals thus live in a state of chronic stress and inflammation; in fact, many people do, because their energy intake vastly exceeds their needs. Hotamisligil calls this chronic energy overload, and the resulting abnormal immune response, metaflammation: metabolic inflammation.
“It is pretty clear that inflammation is a bad actor in obesity,” says Korsmeyer professor of cell biology and medicine Bruce Spiegelman. His lab was the first to establish the mechanism linking obesity to inflammation—in 1993, when he and Hotamisligil, then a doctoral student, discovered that fat cells produce an inflammatory signal that interferes with the body’s ability to regulate blood sugar. This, in turn, increases the risk of developing Type 2 diabetes.
But inflammation in muscle, he says, is “much more complicated.” In fact, “it is likely that you require inflammation in exercise,” and that the inflammatory response should not be suppressed—for example, by taking ibuprofen—because that signal is likely “telling the muscle to remodel.”
Together with Rasmussen professor of immunohematology Diane Mathis, Spiegelman is about to begin studying exercised muscle, a natural system that incorporates and manages inflammation on a regular basis. Mathis studies regulatory T-cells (Tregs), white blood cells that are actively involved in maintaining the internal stability (homeostasis) of tissues. Recently, she has sought to understand the role of Tregs in repairing muscle injured as a consequence of physical trauma or disease.
Now, by studying muscle that has been exercised, she and Spiegelman hope to gain a better understanding of how inflammation is “supposed to happen, and how it eventually resolves.” The sequence, he says, occurs in four steps: “There’s damage, inflammation, resolution of inflammation, and repair. These phases are very different.” He and Mathis hope to learn how these processes unfold—and ultimately, perhaps, to learn how to stimulate, support, or mimic the body’s natural mechanisms of resolution and repair.
Epidemiological studies have helped clarify the importance of lifestyle choices in controlling inflammation. Samia Mora’s 2007 research highlighted the role of exercise. In 2018, she and her colleagues published a study of the Mediterranean diet, which is known to improve cardiovascular health (and also thought to protect against neurodegenerative diseases such as Alzheimer’s and Parkinson’s). Mora examined the effect of this diet on the women who previously participated in the exercise research, 20 years after they had entered the original study. They found that adherence to a diet rich in vegetables, fruit, nuts, legumes, and olive oil, that also includes fish and chicken, but that is very low in red and processed meat and sugary foods or drinks, led to a lower risk of adverse cardiovascular events. As in the exercise study, they found that about a third of the benefit was due to reductions in inflammation.
But some of the diet’s benefit could not be explained, meaning that an untested factor was enhancing its healthful effect. Mora speculates that the diet (which includes probiotic foods such as Greek yogurt) might support the health of the gut microbiome, or might stimulate the parasympathetic nervous system, as exercise does, to help people relax. Alternatively, the diet might be protective against oxidative stress of the kind that comes from pollution or smoking. Perhaps unsurprisingly, each of these possibilities is linked to inflammation.
The great difficulty with interventions involving altered diet and increased exercise is that these healthy habits aren’t aligned with preferences evolved during millennia of food scarcity. People already know what they should be doing—but for most, that knowledge doesn’t change behavior. Humans are hard-wired to conserve energy (see “Born to Rest,” September-October 2016, page 9), for example, and to prefer foods that are fatty, salty, and sugary.
Gelman professor of anaesthesia Charles Serhan has been studying how inflammation ends for 25 years. He realized early on that after the immune system’s soldiers have fought off an invader, the battlefield is littered with bodies: dead cells and scattered debris. The fact that infection has been defeated does not mean that the affected tissue will automatically, passively, return to normal function. There is another process at work, factors that clean up the mess, remove bodies, and repair systems so that the physiological balance within the tissue can be restored. Working with other scientists around the world, he discovered a new class of molecules that actively resolve inflammation. “It turns out that there’s a whole super family of these,” he explains, “and it’s their collapse,” which occurs naturally with aging, that leads to chronic, unresolved immune-system stimulation. “These specialized pro-resolving mediators [SPMs] have been shown in many animal models to reverse inflammation.”
SPMs are unusual immune-signaling molecules, in the sense that they are fats (lipid-derived small molecules), not proteins. They can also mute pain. Their precursors—the substances the body needs in order to synthesize these potent resolving compounds—are the essential fatty acids, including the omega-3 fatty acids EPA and DHA, and arachidonic acid.
In experiments with animals deficient in SPMs, Serhan has shown that injecting SPMs amplifies the magnitude of the healing response, causing injuries to mend more quickly. He emphasizes that reversing inflammation in this way is not the same as blocking it from occurring in the first place. When inflammatory pathways are turned off, there is always a risk that the immune response will be compromised, and that infection will ensue. The SPMs instead work in concert with the immune response by stimulating macrophages “to clear dead cells, debris, and bacteria,” he says. “Then they bring the system back to homeostasis, and begin to push the buttons to signal tissue regeneration.” (They even stimulate the Tregs that Diane Mathis studies to produce an anti-inflammatory signal called IL-10.)
More broadly, he has demonstrated the benefits of such SPMs in preventing neurodegeneration, and is beginning to study their use by professional football players, who suffer high rates of tissue injuries. Serhan has shown that SPMs can be used to control the inflammation that occurs when blood flow resumes to tissues that have been deprived of oxygen during surgery. And he has created an inflammation-resolving mouth rinse that has been tested in periodontal disease and shown to be safe. In earlier experiments, he demonstrated that pro-resolving eye drops can be used to control inflammation in the eye, which “naturally makes buckets of this stuff in tears, so you are bathing normally in pro-resolving mediators.” SPMs are also abundant in the brain, he has found. These are places where avoiding acute inflammation is absolutely critical: infections of the brain can be fatal, and in the eye can lead to blindness.
Colleagues of Serhan’s are using resolvins to control asthma and to stimulate surgical-wound healing. They are also investigating their effects on the microbiome. Earlier animal studies showed that resolvins reduce rheumatoid arthritis.
Because these compounds have not yet been synthesized as pharmaceuticals, maintaining healthy levels of SPMs is best supported by foods rich in the essential fatty acids EPA, DHA, and arachidonic acid. “There’s a reason they are called ‘essential,’” says Serhan. “You can only get them from your diet.” Fish contains all three, although arachidonic acid is also present in chicken, eggs, and beef, and EPA and DHA can be obtained from certain plant sources and algae. It’s ironic, he points out, that veterinary science has ensured that lab animals (and even pets) in the United States eat better than most people do, because animal food is fortified with omega-3s. Most Americans, he believes, don’t eat enough of them.
The scientific study of inflammation has transformed human understanding of this innate biological response. What once were considered merely symptoms—redness, swelling, fever, and pain—are now implicated as the source of many afflictions. For healing, Serhan foresees, we should also look within."