Dr Elisabetta Burchi, MD, MBA
Translational Research Lead at Parasym.
Editor: Dr. Greta Dalle Luche, PhD, Head of R&D
An historical excursus – from “inflammatio” to multiple inflammations
Few concepts in medical theory have been so enduring as that of inflammation. The word, from the Latin “inflammatio”, is thought to have been introduced by the Roman encyclopedist Aulus Cornelius Celsus in the 1st century AD. Later on, galenic medicine adopted the term, defining it according to the five symptoms of rubor (redness), tumor (swelling), calor (heat), dolor (pain), and functio laesa (disturbance of function).
The advent of medical microscopy in the 19th century elucidated what was traditionally explained as resulting from an excessive flow of blood to an injured organ, and today we know that many different cells, cytokines, and pathways contribute to inflammation, now understood as a complex and multi-phased response of the organism to an actual or perceived offense.
It is important to distinguish between acute and chronic inflammation, the former referring to a self-limiting defense mechanism associated with restoration to an homeostatic state, the latter referring to a protracted response often associated with degenerative processes and chronic diseases.
Recent research has revealed that systemic low grade chronic inflammation is associated not only with autoimmune diseases - illnesses that are primarily caused by breaches in immune tolerance and attacks to components of the self, such as multiple sclerosis, rheumatoid arthritis, and Crohn's disease - but also to several metabolic and neoplastic diseases that collectively represent the leading cause of disability and mortality worldwide.
The association between inflammation and chronic metabolic diseases can be interpreted in light of the many layers of evolutionarily conserved interactions that occur between immune response and metabolism. Proper maintenance of this delicate balance is crucial for health and has been identified as a therapeutic target in many of those chronic non-communicable diseases (e.g., cardiovascular disease, diabetes, and cancer). It is now widely recognized that chronic subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction. Consistently with this mechanistic understanding, another term has been coined - “metabolic inflammatory syndrome” - reflecting the association between chronic low grade inflammation and many of the different metabolic diseases - such as obesity, atherosclerosis, dyslipidemia, non-alcoholic fatty liver disease, and hyperglycemia - that lead to insulin resistance and, ultimately, to cardiovascular disease.
Chronic inflammation has also been linked to various steps involved in tumorigenesis, including cellular transformation, proliferation, invasion, and metastasis. In fact, only a minority of all cancers are caused by germline mutations, whereas the vast majority are linked to somatic mutations and environmental factors associated with some form of chronic inflammation: up to 20% of cancers are linked to chronic infections, 30% can be attributed to tobacco smoking and inhaled pollutants (such as silica and asbestos), and 35% can be attributed to dietary factors (20% of cancer burden is linked to obesity).
Another overlooked, but critical component of the inflammatory response is the communication between the systemic immune system and the central nervous system (CNS). We know that there are resident immune cells in the CNS (i.e. microglia) that participate in neurogenesis, synaptic plasticity and maintenance of the neuronal microenvironment, and that the nervous system lays out functional connections with the peripheral immune system, through direct adrenergic, peptidergic, and catecholaminergic innervation of lymphoid organs and indirect modulation of single immune cells via receptors for neuropeptides and neurotransmitters. More recently, accrued evidence on neuro-immune interactions has questioned the historical idea of the brain as immune-privileged. In fact, beyond the presence of microglial cells, the CNS is turned out to be sensitive to peripheral inflammatory events: on the one hand, certain systemic and organ-specific autoimmune diseases, rheumatic mainly, have been associated to neuroinflammation while on the other hand, systemic inflammation has been related to the onset and progression of age-related neurodegeneration and neurodegenerative disorders, such as Alzheimer disease.
How to measure systemic inflammation and specific aspect of the inflammatory response
Systemic inflammation can be assessed using various biochemical or hematological markers routinely measured in common blood tests (i.e. C-reactive protein ) or as ratios derived from these measurements (i.e. high sensitivity C-reactive protein to albumin/prealbumin ratio). An interesting novel measure is the systemic immune-inflammation index (SII), an integrated inflammatory biomarker based on neutrophil, lymphocyte, and platelet counts:
SII= [platelet] x [neutrophil]/ [lymphocyte ratio].
The SII index was initially used to assess the prognosis of patients with solid cancers and coronary heart disease and is now considered to accurately reflect inflammation status. Notably, systemic inflammation as measured by the SII index has been associated with cancer incidence risk, with potential for early identification of disease in the year prior to clinical diagnosis, in particular for colorectal and lung cancer.
In order to have a better resolution and deeper insight on the specific aspects of different immune-inflammatory pathways activated, we can recur to measuring cytokines, potent soluble immune mediators that can be sensitive target biomarkers of pro-inflammatory (i.e. IL-1β, IL-2, IL-8, IL-12p70, TNF-α, IFN-γ), anti-inflammatory (i.e. IL-4, IL-10), or mixed (ie. IL-6, IL-13) activity. Single measurements of selected cytokines have shown to be representative of an individual’s average level of inflammation over time and to be suitable for use in prospective epidemiological and clinical studies.
Boosting or balancing the immune response? An interesting answer from longevity studies
As the aurea mediocritas, or golden mean, would generally suggest “the immune system is much less about exercising power than it is about finding balance”, as Matt Richtel wrote for the New York Times. That means that the maintenance of good health is dependent on an optimal balance between external and internal stressors and the immune response, rather than on the indiscriminate enhancement of the immune response or the severe reduction in immune threats. Consistent with this idea, longevity studies suggest that while low grade inflammation is associated with age-related decline of many functional systems (the so-called “inflammaging”), the balance between pro- and anti-inflammatory mediators is more relevant to healthy aging than the absolute values of the same mediators. It seems that human longevity is paradoxically compatible with a certain degree of age-related increase in the levels of pro-inflammatory markers in blood and tissues, if optimally counter-balanced by the concomitant up-regulation of anti-inflammatory responses. Thus, long living people may be protected against the harmful effects of inflammaging by the presence of high levels of anti-inflammatory molecules, such as soluble TNF receptors.
Moreover, it has been hypothesized that different mechanisms underpinning the inflammatory status may have different consequences on aging. For example, inflammaging has been associated with inflammation induced by DNA damage, but not by muscle contraction. This is consistent with the demonstrated anti-inflammatory role of physical activity.
This new understanding of inflammation as a multifaceted phenomenon supports all the nutritional, behavioral, and neuromodulatory interventions capable of promoting the up-regulation of anti-inflammatory responses when balance between stressors and the immune response is disrupted.
Tools to manage inflammationDiet
Among the modifiable factors that can be manipulated to manage inflammation, diet has a relevant position. The typical western diet, characterized by high intakes of refined sugars (ie. sweets, soft drinks, refined grains), saturated and omega-6 fatty acids (especially processed meats), and salt has been associated with insulin resistance, dyslipidemia, sympathetic nervous system and renin-angiotensin system overstimulation, and oxidative stress - all factors that can strongly contribute to inflammaging. On the other hand, diets characterized by higher intake of whole grains, vegetables, fruits, nuts, and fish are all associated with better inflammatory profiles. A recent interesting study conducted using the UK Biobank data set, highlighted how reducing chronic systemic inflammation via dietary interventions (i.e. diets rich in vegetables, fruit, fish as opposed to diets rich in processed meat) could be an effective primary and/or complementary strategy to increase sleep quality. Crucially, systemic chronic inflammation as measured by C-reactive protein levels and neutrophil to lymphocyte ratio mediated the association between diet health and sleep quality.
Beyond other multiple beneficial functional and psychological effects, exercise is also one of the most effective behavioral interventions to tackle low grade systemic inflammation: moderate physical activity enhances antioxidant response, decreases oxidative stress and pro-inflammatory signals, and consequently improves endothelial function, promoting functional performance and healthy aging. Exercise training was also suggested to improve the defects in the intracellular quality control system – including proteasome functioning and DNA repair systems – which is considered to be an underlying cause of chronic inflammation and aging. Regular exercise has also been reported to increase cellular and mucosal immune function by modulating expression of Toll-like receptors and cytokines.
The cholinergic anti-inflammatory pathway and novel neuromodulation approaches
There is another important protagonist involved in the regulation of the inflammatory state and that can be targeted in order to promote an anti-inflammatory state – the autonomic system.
Around 20 years ago, a research group led by Kevin J. Tracey found that in the presence of peripheral inflammation, afferent signals from the vagal nerve notify the CNS which in turn, activates the efferent vagus nerve. The efferent arm of this “inflammatory reflex” has the goal to counterbalance the inflammatory state. This pathway induces the splenic nerve to release norepinephrine in the spleen which in turn leads to the release of T cell-derived acetylcholine. The neurotransmitter acetylcholine released at the end of this pathway (hence the name “cholinergic anti-inflammatory pathway”) inhibits the release of pro-inflammatory cytokines by macrophages, thus downregulating inflammation.
Notably, indirect and direct techniques, such as meditation and neuromodulation of the vagal nerve, can activate the cholinergic anti-inflammatory pathway., decreasing low grade chronic inflammation associated with many chronic diseases.
Multiple randomized controlled studies conducted with the Parasym device have shown that non-invasive vagus nerve stimulation (nVNS) can reduce pro-inflammatory cytokine levels compared to sham stimulation in different patient populations. In a study conducted in patients with heart failure with preserved ejection fraction, neuromodulation using Paraym device resulted in a significant reduction of TNF-α and IL-8 levels along with improvement in global longitudinal strain and quality of life. Furthermore, Parasym nVNS significantly reduced TNF-α levels along with atrial fibrillation burden in patients with paroxysmal atrial fibrillation compared to placebo. The potential of non-invasive vagal nerve stimulation to positively modulate the immune response has been further demonstrated by another study conducted with the Parasym device in patients with non-small cell lung cancer where vagal nerve stimulation alone or combination with radiotherapy intensified the stimulatory profile of the tumor infiltrated CD8+ T cells tipping the balance from an overall suppressive to a more tumoricidal immune response (**).
Inflammation is one of the most complex and crucial phenomena in the human body being responsible for both the maintenance of homeostasis and good health and the development of irreversibly debilitating diseases. While some increase in baseline inflammation can be physiological and adaptive, protracted or dysregulated inflammation should be controlled and counterbalanced by lifestyle factors or therapeutic interventions, where recommended. nVNS has well-established anti-inflammatory properties through activation of the cholinergic pathway, and has been proven to reduce inflammation in some clinically sensitive patient populations.
In complex pathological and physiological states, such as inflammatory related diseases, single-target therapies may not be fully effective if they do not consider the underlying network of interactions between intertwined genetic, epigenetic, transcriptomic, metabolomic and phenotypic levels. A systemic multimodal approach is likely the most appropriate in order to pave a way for the coming of an era of more personalized care.
OHAD PARNES, “INFLAMMATION”, 2008, THE LANCET
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