Systemic inflammation

Last updated

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. It can contribute to the development or progression of certain conditions such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune and neurodegenerative disorders, [1] and coronary heart disease. [2]

Contents

Mechanisms

Release of pro-inflammatory cytokines 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. [3] 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. [3] Excess advanced glycation end-products attach to RAGE receptors to produce chronic inflammation. [4]

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, interferon gamma, CCL11, and CXCL1, and a proposed measurement of chronic systemic inflammation based on these cytokines (iAge) correlates with immunosenescence and predicts risk for cardiovascular disease, frailty syndrome, and multimorbidity. [5] Damaged proteins and other cellular debris can provoke chronic inflammation in the innate immune system. [6]

Comorbidities

It is firmly established that systemic markers for inflammation predict coronary heart disease complications with or without existing heart disease. [2] Inflammation also plays a role in diabetes risk and new research continues to support this conclusion. [7] Cancer is often caused by chronic inflammation. [8]

Research suggests chronic inflammation plays a major role in COVID-19 morbidity. [9] [10] In severe cases, COVID-19 causes a cytokine storm which contributes to excessive and uncontrolled inflammation of organs, particularly respiratory tissues. [11] [12] If untreated, this increased inflammation can result in reduced immune response, pneumonia, lymphoid tissue damage, and death. [11] Individuals with abnormal cytokine production, such as those with obesity or systemic chronic inflammation, have poorer health outcomes from COVID-19. [9] [10] 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. [9] Anti-viral therapeutic drugs which also reduce inflammation seem to be the most effective treatment, but research is still ongoing. [12] Reactive oxygen species are upregulated during inflammation as part of the immune response to defend against pathogens. [13] However, excessive inflammation causes dangerous levels of reactive oxygen species which cause oxidative stress to tissues. [13] The immune system naturally produces antioxidant compounds to regulate and detoxify reactive oxygen species. [13] Anti-oxidative therapy with supplements such as vitamin C, vitamin E, curcumin, or baicalin is speculated to reduce infection severity in COVID-19, [14] [12] but previous research has not found antioxidants supplementation to be effective in the prevention of other diseases. [15] 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. [12] [16] [17]

Research

While SI may be induced by multiple external factors, research suggests that a lack of control by tolerogenic dendritic cells and T-regulatory cells (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 cells (APCs). Chief among these are dendritic cells (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 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, and autoimmune diseases.

See also

Related Research Articles

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

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". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

<span class="mw-page-title-main">Uveitis</span> Inflammation of the uvea of the eye

Uveitis is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and includes the iris, ciliary body, and choroid. Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, or panuveitic if all parts are involved. Anterior uveitis (iridocyclitis) is the most common, with the incidence of uveitis overall affecting approximately 1:4500, most commonly those between the ages of 20-60. Symptoms include eye pain, eye redness, floaters and blurred vision, and ophthalmic examination may show dilated ciliary blood vessels and the presence of cells in the anterior chamber. Uveitis may arise spontaneously, have a genetic component, or be associated with an autoimmune disease or infection. While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation.

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 immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

Immune dysregulation is any proposed or confirmed breakdown or maladaptive change in molecular control of immune system processes. For example, dysregulation is a component in the pathogenesis of autoimmune diseases and some cancers. Immune system dysfunction, as seen in IPEX syndrome leads to immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX typically presents during the first few months of life with diabetes mellitus, intractable diarrhea, failure to thrive, eczema, and hemolytic anemia. unrestrained or unregulated immune response.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens.

<span class="mw-page-title-main">Autoimmune disease</span> Disorders of adaptive immune system

An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that there are more than 80 recognized autoimmune diseases, with recent scientific evidence suggesting the existence of potentially more than 100 distinct conditions. Nearly any body part can be involved.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging 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 pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

Th17 pathogenic refers to a distinct phenotype of Th17 cells which is associated with immunopathology. The development of the pathogenic phenotype can be shaped by various environmental stimuli and genetic factors. In humans, Th17 pathogenic cells are associated with diseases like multiple sclerosis (MS) or rheumatoid arthritis (RA) and in mice with experimental autoimmune encephalomyelitis (EAE). Th17 pathogenic cells are known to display pro-inflammatory features like expressing transcription factor T-bet and secreting cytokine IFNγ, resembling Th1-like phenotype. Th17 cells are a very heterogenous subset and can switch to display all T helper-like phenotype markers including those typical for Th2, Treg and Tfh.

References

  1. ↑ Furman, David; Campisi, Judith; Verdin, Eric; Carrera-Bastos, Pedro; Targ, Sasha; Franceschi, Claudio; Ferrucci, Luigi; Gilroy, Derek W.; Fasano, Alessio; Miller, Gary W.; Miller, Andrew H. (December 2019). "Chronic inflammation in the etiology of disease across the life span". Nature Medicine. 25 (12): 1822–1832. doi:10.1038/s41591-019-0675-0. ISSN   1546-170X. PMC   7147972 . PMID   31806905.
  2. 1 2 Sattar N, McCarey DW, Capell H, McInnes IB (December 2003). "Explaining how "high-grade" systemic inflammation accelerates vascular risk in rheumatoid arthritis". Circulation. 108 (24): 2957–63. doi: 10.1161/01.CIR.0000099844.31524.05 . PMID   14676136.
  3. 1 2 Sproston, Nicola R.; Ashworth, Jason J. (2018-04-13). "Role of C-Reactive Protein at Sites of Inflammation and Infection". Frontiers in Immunology. 9: 754. doi: 10.3389/fimmu.2018.00754 . ISSN   1664-3224. PMC   5908901 . PMID   29706967.
  4. ↑ Green AS (2018). "mTOR, glycotoxins and the parallel universe". Aging . 10 (12): 3654–3656. doi:10.18632/aging.101720. PMC   6326656 . PMID   30540565.
  5. ↑ Sayed, Nazish; Huang, Yingxiang; Nguyen, Khiem; Krejciova-Rajaniemi, Zuzana; Grawe, Anissa P.; Gao, Tianxiang; Tibshirani, Robert; Hastie, Trevor; Alpert, Ayelet; Cui, Lu; Kuznetsova, Tatiana (2021-07-26). "Author Correction: An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging". Nature Aging. 1 (8): 748. doi: 10.1038/s43587-021-00102-x . ISSN   2662-8465. PMID   37117770.
  6. ↑ Franceschi C, Garagnani P, Salvioli S (2017). "Inflammaging and 'Garb-aging'". Trends in Endocrinology and Metabolism . 28 (3): 199–212. doi:10.1016/j.tem.2016.09.005. hdl: 11585/579512 . PMID   27789101.
  7. ↑ Tsalamandris, Sotirios; Antonopoulos, Alexios S.; Oikonomou, Evangelos; Papamikroulis, George-Aggelos; Vogiatzi, Georgia; Papaioannou, Spyridon; Deftereos, Spyros; Tousoulis, Dimitris (February 2019). "The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives". European Cardiology Review. 14 (1): 50–59. doi:10.15420/ecr.2018.33.1. ISSN   1758-3756. PMC   6523054 . PMID   31131037.
  8. ↑ Bottazzi B, Riboli E, Mantovani A (2018). "Aging, inflammation and cancer". Seminars in Immunology . 40: 74–82. doi:10.1016/j.smim.2018.10.011. PMID   30409538.
  9. 1 2 3 Chiappetta, Sonja; Sharma, Arya M.; Bottino, Vincenzo; Stier, Christine (May 2020). "COVID-19 and the role of chronic inflammation in patients with obesity". International Journal of Obesity. 44 (8): 1790–1792. doi:10.1038/s41366-020-0597-4. ISSN   1476-5497. PMC   7224343 . PMID   32409680.
  10. 1 2 Yang, Jing; Zheng, Ya; Gou, Xi; Pu, Ke; Chen, Zhaofeng; Guo, Qinghong; Ji, Rui; Wang, Haojia; Wang, Yuping; Zhou, Yongning (May 2020). "Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis". International Journal of Infectious Diseases. 94: 91–95. doi:10.1016/j.ijid.2020.03.017. ISSN   1201-9712. PMC   7194638 . PMID   32173574.
  11. 1 2 Tang, Yujun; Liu, Jiajia; Zhang, Dingyi; Xu, Zhenghao; Ji, Jinjun; Wen, Chengping (2020-07-10). "Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies". Frontiers in Immunology. 11: 1708. doi: 10.3389/fimmu.2020.01708 . ISSN   1664-3224. PMC   7365923 . PMID   32754163.
  12. 1 2 3 4 Zabetakis, Ioannis; Lordan, Ronan; Norton, Catherine; Tsoupras, Alexandros (2020-05-19). "COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation". Nutrients. 12 (5): 1466. doi: 10.3390/nu12051466 . ISSN   2072-6643. PMC   7284818 . PMID   32438620.
  13. 1 2 3 Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem; Reddy, Sekhar P.; Malik, Asrar B. (2014-03-01). "Reactive Oxygen Species in Inflammation and Tissue Injury". Antioxidants & Redox Signaling. 20 (7): 1126–1167. doi:10.1089/ars.2012.5149. ISSN   1523-0864. PMC   3929010 . PMID   23991888.
  14. ↑ Wang, Jing-Zhang; Zhang, Rui-Ying; Bai, Jing (2020-08-01). "An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients". International Journal of Cardiology. 312: 137–138. doi:10.1016/j.ijcard.2020.04.009. ISSN   0167-5273. PMC   7133895 . PMID   32321655.
  15. ↑ Katsiki, Niki; Manes, Christos (February 2009). "Is there a role for supplemented antioxidants in the prevention of atherosclerosis?". Clinical Nutrition (Edinburgh, Scotland). 28 (1): 3–9. doi:10.1016/j.clnu.2008.10.011. ISSN   1532-1983. PMID   19042058.
  16. ↑ Rishi, Praveen; Thakur, Khemraj; Vij, Shania; Rishi, Lavanya; Singh, Aagamjit; Kaur, Indu Pal; Patel, Sanjay K. S.; Lee, Jung-Kul; Kalia, Vipin C. (2020-09-28). "Diet, Gut Microbiota and COVID-19". Indian Journal of Microbiology. 60 (4): 420–429. doi:10.1007/s12088-020-00908-0. ISSN   0046-8991. PMC   7521193 . PMID   33012868.
  17. ↑ Di Renzo, Laura; Gualtieri, Paola; Pivari, Francesca; Soldati, Laura; Attinà, Alda; Cinelli, Giulia; Leggeri, Claudia; Caparello, Giovanna; Barrea, Luigi; Scerbo, Francesco; Esposito, Ernesto (2020-06-08). "Eating habits and lifestyle changes during COVID-19 lockdown: an Italian survey". Journal of Translational Medicine. 18 (1): 229. doi: 10.1186/s12967-020-02399-5 . ISSN   1479-5876. PMC   7278251 . PMID   32513197.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.