Chronic systemic inflammation is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the

innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...

. It can contribute to the development or progression of certain conditions such as

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

non-alcoholic fatty liver disease An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...

and neurodegenerative disorders, and

coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

Mechanisms

Release of pro-inflammatory

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s and activation of the innate immune system may be the result of either external (biological or chemical agents) or internal (genetic mutations/variations) factors. The cytokine

Interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

and

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin ...

are common inflammatory markers used to diagnose systemic inflammation risk. Baseline C-reactive protein levels deviate due to natural genetic variation, but significant increases can result from risk factors such as smoking, obesity, lifestyle, and high blood pressure. Excess

advanced glycation end-product Advanced glycation end-products (AGEs) are proteins or lipids that become Glycation, glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as dia ...

s attach to RAGE receptors to produce chronic inflammation. Systemic chronic inflammation increases with age (also known as inflammaging) due to unresolved acute inflammation and an individual's exposome. Age-related systemic chronic inflammation is associated with several cytokines including CXCL9,

TRAIL A trail, also known as a path or track, is an unpaved lane or a small paved road (though it can also be a route along a navigable waterways) generally not intended for usage by motorized vehicles, usually passing through a natural area. Ho ...

interferon gamma Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...

CCL11 C-C motif chemokine 11 also known as eosinophil chemotactic protein and eotaxin-1 is a protein that in humans is encoded by the CCL11 gene. This gene is encoded on three exons and is located on chromosome 17. Function CCL11 is a small cytokin ...

, and

CXCL1 The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infecti ...

, and a proposed measurement of chronic systemic inflammation based on these cytokines (iAge) correlates with immunosenescence and predicts risk for

frailty syndrome Frailty or frailty syndrome refers to a state of health in which older adults gradually lose their bodies' in-built reserves and functioning. This makes them more vulnerable, less able to recover and even apparently minor events (infections, envi ...

, and

multimorbidity Multimorbidity, also known as multiple long-term conditions (MLTC), means living with two or more chronic illnesses. For example, a person could have diabetes, heart disease and Depression (mood), depression at the same time. Multimorbidity can h ...

. Damaged proteins and other cellular debris can provoke chronic inflammation in the

Comorbidities

It is firmly established that systemic markers for inflammation predict coronary heart disease complications with or without existing heart disease. Inflammation also plays a role in diabetes risk and new research continues to support this conclusion.

Cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

is often caused by chronic inflammation. Research suggests chronic inflammation plays a major role in

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...

morbidity. In severe cases, COVID-19 causes a

cytokine storm A cytokine storm, also called hypercytokinemia, is a pathological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Cytok ...

which contributes to excessive and uncontrolled inflammation of organs, particularly respiratory tissues. If untreated, this increased inflammation can result in reduced immune response,

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

, lymphoid tissue damage, and death. Individuals with abnormal cytokine production, such as those with obesity or systemic chronic inflammation, have poorer health outcomes from COVID-19. Elevated cytokine production alters the innate immune response which leads to abnormal T-cell and B-Cell function that decreases control of viral replication and host defense. Anti-viral therapeutic drugs which also reduce inflammation seem to be the most effective treatment, but research is still ongoing.

Reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

are upregulated during inflammation as part of the immune response to defend against pathogens. However, excessive inflammation causes dangerous levels of reactive oxygen species which cause

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

to tissues. The immune system naturally produces

antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

compounds to regulate and detoxify reactive oxygen species. Anti-oxidative therapy with supplements such as

vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...

vitamin E Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen speci ...

curcumin Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...

, or

baicalin As baicalin is a flavone glycoside, it is a flavonoid. It is the glucuronide of baicalein. Natural occurrences Baicalin is found in several species in the genus ''Scutellaria'', including ''Scutellaria baicalensis'', and ''Scutellaria laterifl ...

is speculated to reduce infection severity in COVID-19, but previous research has not found antioxidants supplementation to be effective in the prevention of other diseases. Shifting from the typical

western diet The Western pattern diet is a modern dietary pattern originating in the industrialized West which is generally characterized by high intakes of pre-packaged foods, refined grains, red and processed meat, high-sugar drinks, candy and swe ...

to a

Mediterranean diet The Mediterranean diet is a concept first proposed in 1975 by the American biologist Ancel Keys and chemist Margaret Keys. The diet took inspiration from the eating habits and traditional food typical of Crete, much of the rest of Greece, and s ...

plant-based diet A plant-based diet is a diet consisting mostly or entirely of plant-based foods. It encompasses a wide range of dietary patterns that contain low amounts of animal products and high amounts of fiber-rich plant products such as vegetables ...

may improve COVID-19 health outcomes by reducing prevalence of comorbidities (i.e. obesity or hypertension), decreasing intake of pro-inflammatory foods, and increasing consumption of anti-inflammatory and antioxidant nutrients.

Research

While systemic inflammation may be induced by multiple external factors, research suggests that a lack of control by tolerogenic

dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

s and

T-regulatory cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immu ...

s (Treg) is possibly the primary risk factor. In functioning immune responses, T-helper and T-cytotoxic cells are activated by presentation of antigens by

antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...

s (APCs). Chief among these are

s (DCs). When a DC presents an antigen to a Treg cell, a signal is then sent to the nucleus of the DC, resulting in the production of

indoleamine 2,3-dioxygenase Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO ) is a heme-containing enzyme physiologically expressed in a number of Tissue (biology), tissues and Cell (biology), cells, such as the small intestine, lungs, female genital tract or placenta. I ...

(IDO). IDO inhibits T cell responses by depleting

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

and producing

kynurenine -Kynurenine is a metabolite of the amino acid -tryptophan used in the production of niacin. Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygena ...

, which is toxic to the cell. Individuals susceptible to developing chronic systemic inflammation appear to lack proper functioning of Treg cells and TDCs. In these individuals, a lack of control of inflammatory processes results in multiple chemical and food intolerances, and autoimmune diseases.

References

{{Reflist Inflammations

Mechanisms

Comorbidities

Research

See also

References