Chronic systemic inflammation (SI) is the result of release of

pro-inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...

s 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, h ...

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 ap ...

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 and neurodegenerative disorders, and coronary heart disease.

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 autocrin ...

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 and C-reactive protein 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) 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 An environmental factor, ecological factor or eco factor is any factor, abiotic or biotic, that influences living organisms. Abiotic factors include ambient temperature, amount of sunlight, and pH of the water soil in which an organism lives. Bi ...

. 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. Th ...

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 Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the h ...

and predicts risk for

, frailty syndrome, 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 ...

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 COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...

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 severity ...

, 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 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 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 lubricant ...

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) an ...

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 vitami ...

, Curcumin, 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 lateri ...

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 or plant-based diet 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. ...

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 using ...

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, 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