by Sara Gottfried, MD; Annalouise O’Connor, PhD, RD; Lewis Chang, PhD
If we go back a few decades, scientists and clinicians considered the leading public health killers—such as heart disease, cancer, Alzheimer’s disease, diabetes—to be separate diseases. Now we know they have a common root cause: inflammation, the process by which the body’s white blood cells are recruited and activated for a specific purpose. Acute inflammation is triggered to help fight an infection or illness, or to heal an injury, but the problem starts when inflammation doesn’t resolve. As a clinician, understanding the switch from acute inflammation to chronic inflammation is worthy of your attention, because the hope is that if you address the root cause, you may be able to help your patients not just with their risk of myocardial infarction or insulin resistance, but perhaps you might even simultaneously address their risk globally of chronic disease.
First, a caveat. Inflammation has become a buzz word, a catch-all phrase. There isn’t just one type of chronic inflammation. There are different types of immune responses. The type of inflammation that leads to chronic joint pain may be different from the type of inflammation associated with cancer, which may be a different type from the inflammation underlying many cases of depression. There are many immunological cell types communicating via many signals. There are adaptive and innate immune pathways. And we are at the learning-to-crawl stage with understanding the role of nutrition, nutrigenomics, supplements, and personalized lifestyle medicine in the resolution of chronic inflammation. Still, our understanding of unresolved inflammation has progressed to the point that we can now define both deficits of inflammation resolution, and cellular resilience, the ability to return to homeostasis.
Consider the analogy offered by Siddhartha Mukherjee, MD, DPhil paraphrased here: Imagine inflammation as a fuse box in an old house that you just bought. You want to find the switch to turn on the light in the living room, or to turn off the alarm, but the circuitry is baffling. Some switches are unlabeled. Some are labeled but in a foreign language. Some read: Do Not Touch.1 So our task is to understand the switches and define the labels, then see what each switch does in the “house” of the body.
We evolved to become inflamed. We needed inflammation to cope with pathogens, predators, rivals, and physical injury. A finely-tuned inflammatory response is a vital defense mechanism against harmful stimuli of infectious and noninfectious origin. However, many modern lifestyle and environmental factors disrupt and overwhelm our natural defenses, leading inflammation to go sideways. Instead of resolving as intended, we now face an epidemic of uncontrolled and chronic inflammation, putting our patients at increased risk of many noncommunicable diseases. How we support our natural resilience in the face of this onslaught of stimuli strongly influences health and function. As practitioners, our goal is help our patients to thrive rather than merely survive. Increasingly, thriving requires the resolution of inflammation.
We all know the downstream benefits of cultivating psychological and emotional resilience, but the scientific literature now point in a new direction: that we can and must promote physiological and cellular resilience too. Inflammation resilience is a critical component of physiological and cellular resilience. This resolution response is an active and highly coordinated one, led by a group of lipid mediators, known as specialized pro-resolving mediators (SPMs). SPMs are critical to our body’s ability to return to homeostasis—to “bounce back” from inflammatory stressors. The discovery of inflammation resolution and SPMs provides us with a new way of viewing and understanding inflammation and how we can support cellular resilience and thus our overall health.
In this article, we will first discuss the concept of resilience, particularly physiological and cellular resilience. We will then describe the two phases of a healthy, balanced, and self-limited inflammatory response and how this restores resilience at the physiological and cellular level. Finally, we will discuss conditions associated with both declining cellular resilience and an inflammation resolution deficit.
Cellular resilience is foundational to health
Resilience, according to the American Psychological Association (APA), is “the process of adapting well in the face of adversity, trauma, tragedy, threats, or significant sources of stress—such as family and relationship problems, serious health problems, or workplace and financial stressors. It means ‘bouncing back’ from difficult experiences.”2 Resilience is part of basic homeostasis, meaning that most people normally have the capacity for resilience though it can be bolstered through interlinked coping strategies such as establishing caring and supportive relationships, developing the capacity to make realistic plans and to carry them out, having a positive self-view, managing strong feelings and impulses, and learning the skills to communicate and problem-solve.3
While resilience at the psychological and emotional level is essential to risk reduction of chronic disease and involves signaling of the hypothalamic-pituitary-adrenal axis, we need to extend the concept. Our cells and tissues are exposed to physical and environmental stressors, ranging from toxins and heavy metals, air and water pollution, to viral and bacterial infections.4 Therefore, resilience at this level can be defined more broadly as the capacity of a system (our cells and tissues are complex systems) to navigate stressors while maintaining function.5
Our bodies have multiple built-in coping strategies to manage stressors at the physiological and cellular levels, including the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic drive, innate and adaptive inflammatory responses, oxidative stress response, and energy repartitioning, just to name a few.6,7 Taking a systems biology view of the response to stressors, we see that these levers of resilience are interconnected and are also influenced by the body’s baseline status—think health condition, sex hormones, environment, diet, and lifestyle—which will prime the body’s response to stressors and influence resilience over time. This is why resilience varies among people and also over the course of a person’s life.
Inflammaging and declining resilience
Accelerated aging is an important example of declining physiological and cellular resilience. Increasing biological age is linked with a reduced capacity to respond to multiple types of stressors including glucose fluctuations, changes in temperature, mechanical strain, immune triggers, emotional and psychological stress, and loss of function.8 Changing responses to stressors, diminished homeostasis, and declining resilience have been seen in experimental models of biological aging.9,10 One of the factors most prominently linked to aging is “inflammaging,” a progressive increase in a low-grade, nonresolving, proinflammatory state. The concept of inflammaging was first introduced by Professor Claudio Frenceschi in 2000.11
A closer look at the two phases of a typical inflammatory response, including the commonly overlooked resolution phase, will help us understand how supporting a balanced inflammatory response with complete resolution can reinforce the body’s natural resilient state or, on the flip side, show how incomplete resolution, or a resolution deficit, can contribute to increased vulnerability and declining cellular resilience.
Inflammation: friend or foe?
The ability to mount an inflammatory response is critical to protection and survival. We have evolved finely tuned inflammatory mechanisms geared toward responding and protecting from harmful stressors such as infection (e.g., bacterial, viral, fungal, parasitic), tissue damage (e.g., from reduced blood flow or trauma), exposure to physical or chemical agents (e.g., burns, frostbite, environmental chemicals), foreign objects (e.g., splinters, dirt), or hypersensitivity reactions.12 Once immune cells identify a stressor, a cascade of proinflammatory events are set in motion. Proinflammatory mediators such as histamine, cytokines, chemokines, and eicosanoids [including leukotrienes (LTx) and prostaglandins (PGs)] help increase blood flow and vascular permeability, allowing the further recruitment and activation of proinflammatory immune cells (mainly neutrophils and monocytes) to the affected area.12 These events form what is known as the inflammation initiation phase, the body’s response to stressors, and coordinate the activities associated with redness, heat, swelling, pain, and loss of function, the five cardinal signs of inflammation.12
Although critical for survival, over- or inappropriate activation of these initiation responses can lead to a persistent, proinflammatory state that underpins the majority of chronic diseases prevalent today.13 To avoid these consequences, the initiation phase needs to be balanced with a robust counter-regulatory response.
Inflammation resolution—an important level of cellular and physiological resolution
The resolution phase of any inflammatory response is critical to provide balance to the activities that take place during the initiation phase. Inflammation resolution acts as a counter-regulatory force with the goal of reducing the magnitude of further initiation activities, clearing affected tissue following the aftermath of the initiation phase, and supporting the tissue repair, healing, and return to homeostasis.14,15 In other words, resolution helps affected tissues respond more appropriately to the inflammatory stressor and “bounce back”—promoting overall physiological and cellular resilience.
Over the past 30 years, scientists led by Dr. Charles Serhan (PhD, DSc) at Harvard Medical School have discovered the mechanisms driving of inflammation resolution and a group of lipid mediators known as specialized pro-resolving mediators (SPMs) that coordinate the resolution response. Before the discovery of SPMs it was believed that inflammation passively faded away as the proinflammatory signals and cells were diluted over time. However, cells involved in inflammatory responses cannot act without “marching orders” from various mediators. Indeed, recent breakthroughs in research determined that SPMs are produced by surrounding resident cells and immune cells and actively orchestrate inflammation resolution events. These resolution events have been described as removal, restoration, regeneration, remission, and relief, the five cardinal signs of resolution.16
Specialized pro-resolving mediators—conductors of the resolution orchestra
SPMs are produced in the body from long-chain polyunsaturated fatty acids via a series of enzymatic steps. There are several classes of SPMs, which all work together in a coordinated manner to actively resolve inflammation. Eicosapentaenoic acid (EPA) can give rise to a group of SPMs known as E-series resolvins.17 18-hydroxyeicosapentaenoic acid (18-HEPE) is a key lipid mediator produced along this pathway and acts as the precursor to the full range of E-series resolvins.17 Docosahexaenoic acid (DHA) can give rise to another group of resolvins known as D-series resolvins.17 17-hydroxydocosahexaenoic acid (17-HDHA) is a key lipid mediator produced along this pathway and acts as the precursor to a full range of D-series resolvins.17 Protectins, neuroprotectins, and maresins are additional classes of SPMs that can be produced from DHA.17 Lipoxins are a group of SPMs formed from arachidonic acid (AA).17 Recently, interesting classes of SPMs such as T-series resolvins, specific D-series resolvins, and maresins have been discovered to be derived from docosapentaenoic acid (DPA).18
The hallmarks of SPM activity and the resolution response have been described as follows:19
- Termination of neutrophil infiltration: The “marching orders” from the initiation phase open the gate, allowing “soldiers” (neutrophils) with powerful weapons to perform combat duties at the affected site. But when “enemies” have been removed, new orders are needed. Otherwise additional combat units will continue to march in and end up causing collateral damage.
- Timely apoptosis of existing neutrophils followed by active clearance of apoptotic neutrophils and debris by macrophages (phagocytosis/efferocytosis): Task completed, the existing combat units (activated neutrophils) are still lingering around the affected site. SPMs signal them to undergo programmed cell death so they don’t cause damage to surrounding tissues with their histotoxic contents. Then SPMs signal another type of cells, macrophages, to ingest these dead cells so that the affected area can be restored and returned to a normal state. In general, the act of engulfing and ingesting cells, particles, and microbes by another cell is called phagocytosis. The important job of removing dead neutrophils by macrophages during the resolution phase is specifically called efferocytosis.20
- Stimulation of macrophages into a proresolution phenotype: Macrophages are highly plastic cells that can differentiate to (or shift between) proinflammatory (classically termed M1) or anti-inflammatory (classically termed M2) phenotypes based on environmental cues.21 Efferocytosis results in molecular and functional shifts in macrophages that resemble M2 phenotype.22 They stop producing proinflammatory cytokines and lipid mediators (e.g. LTs and PGs) and begin to produce SPMs. This production facilitates a proresolution environment that supports regeneration, repair, and return to homeostasis.
- Decreased production of proinflammatory mediators and increased productions of anti-inflammatory mediators: SPMs act as a counter-regulatory force in a balanced inflammatory response. By reducing the proinflammatory cells entering the area and by promoting a more anti-inflammatory and proresolving immune cell phenotype, SPMs have been shown to reduce proinflammatory signals present in tissue.
- Tissue repair and return to homeostasis
The process of switching from an environment containing high levels of proinflammatory mediators such as PGs and LTs, which initiate inflammation, to one containing high levels of SPMs, which resolve inflammation, is known as lipid mediator class switching.23 This process of switching to resolution is built into a healthy, normal inflammatory response and starts when inflammation has been initiated—a concept described in the resolution literature and by Dr. Serhan as “alpha signals omega,” or the beginning signals the end.24 PGs, which are central to upregulation of proinflammatory processes, also activate part of the machinery involved in making SPMs. This is an example of the body’s innate and ordinary resilience mechanisms. However, there are situations when this normal protective response is not effective, lipid mediator class switching appears to be subpar, leading to a resolution deficit and reduced resilience.
Resolution failure and declining cellular resilience
Dysregulation of the resolution phase may leave an inflammatory response unresolved, thereby causing chronic, low-grade inflammation. For instance, if the dead and dying neutrophils that entered the tissue during the initiation phase are not removed efficiently (a hallmark of the resolution), they may become necrotic and release harmful contents that damage surrounding tissues, amplifying the inflammatory response or leading to inappropriate autoimmune response.25
Aging and obesity are considered states of chronic low-grade inflammation—and may also be viewed as states of reduced resilience—as will be discussed below. A background of elevated inflammatory burden and an increase in proinflammatory cells, coupled with a resolution deficit that has been demonstrated in these states, can prime the system to respond in a proinflammatory way, negatively impacting overall resilience.
Aging (“Inflammaging”): A preclinical model of aging mice showed an exacerbated inflammatory response (more inflammatory cells and mediators) and an impaired ability to resolve inflammation in response to the same inflammatory challenge (intraperitoneal injection with Zymosan A, a type of yeast cell wall particles) compared with younger mice.26 The ability of the macrophages to clear dead or dying cells (an important activity during the resolution phase) was also significantly lower in the older mice.26 The resolution index, a metric of how proinflammatory cells are reducing in number, was 85% lower in older mice. Interestingly, the lipid mediator profile in aged animals was altered, with lower levels of SPMs including D-series resolvin 1 (RvD1), maresin-1 (MaR1), and lipoxin B4 (LXB4) and a greater proportion of proinflammatory lipid mediators including LTB4 and PGF2α.27 The more exacerbated proinflammatory response and slower return to baseline levels indicates a resolution deficit and reduced resilience to the inflammatory challenge.
Obesity and metabolic diseases: Visceral adipose tissue of individuals with obesity exhibit an imbalance between the levels of SPMs and proinflammatory mediators including LTs and PGs.28 This represents a potential impairment in lipid mediator class switching, resulting in the promotion of a more proinflammatory environment. These results echo earlier work in mice, which demonstrated that resolvin concentration of adipose tissue was decreased and that even when fed a DHA-enriched diet, levels of 17-HDHA and resolvins could not be increased to levels seen in the leaner mice.29
This reduced ability to use EPA and DHA to increase lipid mediators linked with resolution was also seen in men and women with metabolic syndrome. When supplemented for 4 weeks with 4 g of fish oil (providing 2.4 g of EPA and DHA), the individuals with metabolic syndrome had a blunted increase in 17-HDHA and 18-HEPE status in blood compared with men and women with a healthy body weight, suggesting that EPA and DHA may be less effective in improving SPM status in metabolic syndrome.30
More recently, white blood cells from individuals with obesity were shown to have an impaired ability to produce resolvins.31 Importantly, providing 17-HDHA and 18-HEPE to white blood cells from the participants of the obese group could override the impairment in SPM production and promote a rebalance between the proinflammatory and proresolving lipid mediators. These results support the concept that obesity is a condition of resolution failure, and also suggest that providing 17-HDHA and 18-HEPE can help rescue the resolution deficit seen in obesity.31
The reduced SPM status and imbalance between proinflammatory and proresolving lipid mediators contributes to inflammation within the adipose tissue,32 which is a central driver of insulin resistance.33 Insulin-resistant tissues are less metabolically flexible and less resilient in the face of changing dietary and fuel availability patterns.34 In addition to this potential impact on metabolism, recent work in animal models of obesity has demonstrated that reduced status of SPMs may be linked with impaired B-cell numbers and antibody production.35 Obesity is associated with increased susceptibility to infection,36 and this new work on resolution deficit and B-cell activity represents a possible mechanism behind this impaired resilience.
While a patient’s ability to mount an inflammatory response is critical for a well-functioning and protective response to many challenges, the specific manner in which the body deals with inflammation and resolves it are key to health and function. A balanced inflammatory response that confers protection but also promotes restoration, healing, and resilience involves an active resolution phase. Our knowledge of inflammation resolution provides us with this expansive view of a well-balanced inflammatory cascade as a key component of resilience and healing. As Dr. Mukherjee eloquently describes in his analogy for inflammation, we are better able to turn on the lights in the living room and turn off the alarm.
Dr. Serhan, who pioneered the discovery of SPMs and our understanding of resolution, commented: “This I feel is a concept that has been lost with time. In the earliest writings on the treatment of inflammation we found in the canons of medicine and its movement to Europe around the 11th century, this concept of resolvents—and I consider the SPMs as candidates as immunoresolvents—to stimulate resolution rather than to use—as we do today—inhibitors to block various aspects of the innate inflammatory response.”37
When asked what excited him about the future of research on inflammation resolution, he is “most excited that the thoughts about stimulating resolution are emerging for the general practitioners as well as for specialized clinicians in many fields….”37
(To view the interview with Dr. Serhan, click here.)
While the body of preclinical and clinical research on SPMs in a variety of therapeutic areas is growing, the concept of improving inflammation resolution is evolving into reality. For instance, novel SPM-rich nutritional formulas are being utilized to manage inflammatory conditions in the clinic, and medical devices designed to deliver SPMs (such as for the prevention of restenosis following angioplasty) are currently being funded and developed. Questions remain as we endeavor to understand more about the various phenotypes of inflammation and deficits of inflammation resolution, but we are now in an era where resolution deficits may be addressed in a personalized manner and managed in order to enhance patient resilience and improve their overall health.
- The New York Times Magazine. Mukherjee S. What we learn when two ruthless killers, heart disease and cancer, reveal a common root. https://www.nytimes.com/2017/09/27/magazine/can-heart-disease-shed-light-on-cancer.html. Accessed May 14, 2019.
- Newman R. APA’s resilience initiative. Prof Psychol Res Pr. 2005;36(3):227-229.
- Levine S. Psychological and social aspects of resilience: a synthesis of risks and resources. Dialogues Clin Neurosci. 2003;5(3):273-280.
- Münzel T et al. Environmental stressors and their impact on health and disease with focus on oxidative stress. Antioxid Redox Signal. 2018;28(9):735-740.
- Smirnova L et al. Cellular resilience. ALTEX. 2015;32(4):247-260.
- Herman JP et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6(2):603-621.
- Muralidharan S et al. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol. 2013;94(6):1167-1184.
- Pomatto LCD et al. The role of declining adaptive homeostasis in ageing. J Physiol. 2017;595(24):7275-7309.
- Kirkland JL et al. Resilience in aging mice. J Gerontol A Biol Sci Med Sci. 2016;71(11):1407-1414.
- Epel ES et al. Stress biology and aging mechanisms: toward understanding the deep connection between adaptation to stress and longevity. J Gerontol A Biol Sci Med Sci. 2014;69(Suppl 1):S10-S16.
- Franceschi C et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244-254.
- Kumar V et al. Chapter 2. Inflammation and Repair. Robbins Basic Pathology. 9th ed: Saunders; 2012.
- Prasad S et al. Age-associated chronic diseases require age-old medicine: role of chronic inflammation. Prev Med. 2012;54 Suppl:S29-37.
- Serhan CN. A search for endogenous mechanisms of anti-inflammation uncovers novel chemical mediators: missing links to resolution. Histochem Cell Biol. 2004;122(4):305-321.
- Serhan CN et al. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med. 2000;192(8):1197-1204.
- Basil MC et al. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol. 2016;16(1):51-67.
- Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.
- Weylandt KH. Docosapentaenoic acid derived metabolites and mediators – The new world of lipid mediator medicine in a nutshell. Eur J Pharmacol. 2016;785:108-115.
- Serhan CN et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21(2):325-332.
- Dalli J et al. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012;120(15):e60-72.
- Dalli J et al. Macrophage proresolving mediators-the when and where. Microbiol Spectr. 2016;4(3).
- Ariel A et al. New lives given by cell death: macrophage differentiation following their encounter with apoptotic leukocytes during the resolution of inflammation. Front Immunol. 2012;3:4.
- Levy BD et al. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;2(7):612-619.
- Recchiuti A. Immunoresolving lipid mediators and resolution of inflammation in aging. J Gerontol Geriat Res. 2014;3:151.
- Lawrence T et al. Chronic inflammation: a failure of resolution? Int J Exp Pathol. 2007;88(2):85-94.
- Arnardottir HH et al. Aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines. J Immunol. 2014;193(8):4235-4244.
- Arnardottir HH et al. Resolvin D3 Is dysregulated in arthritis and reduces arthritic inflammation. J Immunol. 2016;197(6):2362-2368.
- Titos E et al. Signaling and immunoresolving actions of resolvin D1 in inflamed human visceral adipose tissue. J Immunol. 2016;197(8):3360-3370.
- Neuhofer A et al. Impaired local production of proresolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation. Diabetes. 2013;62(6):1945-1956.
- Barden AE et al. Specialized proresolving lipid mediators in humans with the metabolic syndrome after n-3 fatty acids and aspirin. Am J Clin Nutr. 2015;102(6):1357-1364.
- López-Vicario C et al. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 2019:fj201802587R.
- Clària J et al. Pro-resolving actions of SPM in adipose tissue biology. Mol Aspects Med. 2017;58:83-92.
- Yaribeygi H et al. Insulin resistance: Review of the underlying molecular mechanisms. J Cell Physiol. 2019;234(6):8152-8161.
- Goodpaster BH et al. Metabolic flexibility in health and disease. Cell Metab. 2017;25(5):1027-1036.
- Crouch MJ et al. Frontline science: a reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody. J Leukoc Biol. 2018.
- Huttunen R et al. Obesity and the risk and outcome of infection. Int J Obes (Lond). 2013;37(3):333-340.
- Metagenics Institute. What excites you about the SPMs research you are involved in? https://www.metagenicsinstitute.com/video/excites-spms-research-involved/. Accessed May 14, 2019.
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.
Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.
Annalouise O’Connor, PhD, RD trained as an RD and worked in clinical and public health settings. Dr. O’Connor completed her PhD in the Nutrigenomics Research Group at University College Dublin (Ireland) and postdoctoral work at the UNC Chapel Hill Nutrition Research Institute.
Lewis Chang, PhD is Scientific Editorial Manager of R&D at Metagenics. Dr. Chang received his PhD in Nutritional Sciences at University of Washington, along with his MS in Nutrition and Public Health from Teachers College, Columbia University and BS in Pharmacy from National Taiwan University. Prior to joining Metagenics, he conducted dissertation research and completed a research assistantship and postdoctoral fellowship at the Fred Hutchinson Cancer Research Center in Seattle, WA. Dr. Chang has authored or co-authored and managed the publication of over 30 peer-reviewed journal articles and numerous scientific abstracts and posters. He has quite a green thumb, enjoys opera, theater and jazz, and loves cooking, collecting art, and learning to play gypsy jazz guitar.