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

innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

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

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...

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), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

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 peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...

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. Smooth ...

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. Systemic chronic inflammation increases with age (also known as

inflammaging Inflammaging (also known as inflamm-aging or inflamm-ageing) is a chronic, sterile low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related path ...

) due to unresolved

acute inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

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 small road usually passing through a natural area. In the United Kingdom and the Republic of Ireland, a path or footpath is the preferred term for a pedestrian or hiking trail. ...

interferon gamma Interferon gamma (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. Wheelock ...

, CCL11, 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 is a common geriatric syndrome that embodies an elevated risk of catastrophic declines in health and function among older adults. Frailty is a condition associated with ageing, and it has been recognized for centuries. It is also a marker ...

, 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 at the same time. Multimorbidity can have a significan ...

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. Research suggests chronic inflammation plays a major role in

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quick ...

morbidity. In severe cases, COVID-19 causes a

cytokine storm A cytokine storm, also called hypercytokinemia, is a physiological 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. Norma ...

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 inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...

, 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, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

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 compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubrica ...

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 and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...

Vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vi ...

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, cosmet ...

, 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 to a

Mediterranean diet The Mediterranean diet is a diet inspired by the eating habits of people who live near the Mediterranean Sea. When initially formulated in the 1960s, it drew on the cuisines of Greece, Italy, France and Spain. In decades since, it has also incor ...

plant-based diet A plant-based diet is a diet consisting mostly or entirely of plant-based foods. Plant-based diets encompass a wide range of dietary patterns that contain low amounts of animal products and high amounts of plant products such as vegetables, fru ...

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

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. Th ...

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 immunosu ...

s (Treg) is possibly the primary risk factor for the development of SI. 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 that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes usi ...

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 (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 aromatic ...

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-dioxygenase ...

, 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, autoimmune diseases.

References

{{Reflist Inflammations

Mechanisms

Comorbidities

Research

See also

References