Editing Inflammation (section)

== Disorders ==
[[File:Asthma (Lungs).png|thumb|215x215px|Asthma is considered an inflammatory-mediated disorder. On the right is an inflamed airway due to asthma.]]
[[File:CD colitis 2.jpg|thumb|209x209px|Colitis (inflammation of the colon) caused by [[Crohn's disease]].]]
Inflammatory abnormalities are a large group of disorders that underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, as demonstrated in both [[allergic reaction]]s and some [[myopathies]], with many [[immune system disorder]]s resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer, [[atherosclerosis]], and [[ischaemic heart disease|ischemic heart disease]].<ref name="robspath" />

Examples of disorders associated with inflammation include:
{{div col|colwidth=25em}}
* [[Acne vulgaris]]
* [[Asthma]]
* [[Autoimmune disease]]s
* [[Autoinflammatory disease]]s
* [[Celiac disease]]
* [[Asymptomatic inflammatory prostatitis|Chronic prostatitis]]
* [[Ulcerative colitis|Colitis]]
* [[Diverticulitis]]
* [[Familial Mediterranean Fever]]
* [[Glomerulonephritis]]
* [[Hidradenitis suppurativa]]
* [[Hypersensitivity|Hypersensitivities]]
* [[Inflammatory bowel disease]]s
* [[Interstitial cystitis]]
* [[Lichen planus]]
* [[Mast Cell Activation Syndrome]]
* [[Mastocytosis]]
* [[Otitis]]
* [[Pelvic inflammatory disease]]
* [[Peripheral ulcerative keratitis]]
* [[Pneumonia]]
* [[Reperfusion injury]]
* [[Rheumatic fever]]
* [[Rheumatoid arthritis]]
* [[Rhinitis]]
* [[Sarcoidosis]]
* [[Transplant rejection]]
* [[Vasculitis]]
{{div col end}}

=== Atherosclerosis ===

{{main|Atherosclerosis}}
Atherosclerosis, formerly considered a [[lipid]] storage disorder, is now understood as a chronic inflammatory condition involving the arterial walls.<ref name="libby2021">{{cite journal |vauthors=Libby P |title=Inflammation during the life cycle of the atherosclerotic plaque |journal=Cardiovascular Research |volume=117 |issue=13 |pages=2525–2536 |date=November 2021 |pmid=34550337 |pmc=8783385 |doi=10.1093/cvr/cvab303}}</ref> Research has established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, the thrombotic complications from it.<ref name=libby2021/> These new findings reveal links between traditional risk factors like cholesterol levels and the underlying mechanisms of [[atherogenesis]].

Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to people.<ref name="libby2021" /> For instance, elevation in markers of inflammation predicts outcomes of people with [[acute coronary syndrome]]s, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker [[C-reactive protein]], prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors, such as LDL levels.<ref>{{cite journal | vauthors = Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A | title = Role of inflammation in atherosclerosis | journal = Journal of Nuclear Medicine | volume = 48 | issue = 11 | pages = 1800–1815 | date = November 2007 | pmid = 17942804 | doi = 10.2967/jnumed.107.038661 }}</ref><ref name=libby2021/>

Moreover, certain treatments that reduce coronary risk also limit inflammation. Notably, lipid-lowering medications such as [[statin]]s have shown anti-inflammatory effects, which may contribute to their efficacy beyond just lowering LDL levels.<ref>{{cite journal | vauthors = Morofuji Y, Nakagawa S, Ujifuku K, Fujimoto T, Otsuka K, Niwa M, Tsutsumi K | title = Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer | journal = Pharmaceuticals | volume = 15 | issue = 2 | pages = 151 | date = January 2022 | pmid = 35215263 | pmc = 8877351 | doi = 10.3390/ph15020151 | doi-access = free }}</ref> This emerging understanding of inflammation's role in atherosclerosis has had significant clinical implications, influencing both risk stratification and therapeutic strategies.

==== Emerging treatments ====

Recent developments in the treatment of atherosclerosis have focused on addressing inflammation directly. New anti-inflammatory drugs, such as monoclonal antibodies targeting IL-1β, have been studied in large clinical trials, showing promising results in reducing cardiovascular events.<ref>{{cite journal | vauthors = Szekely Y, Arbel Y | title = A Review of Interleukin-1 in Heart Disease: Where Do We Stand Today? | journal = Cardiology and Therapy | volume = 7 | issue = 1 | pages = 25–44 | date = June 2018 | pmid = 29417406 | pmc = 5986669 | doi = 10.1007/s40119-018-0104-3 }}</ref> These drugs offer a potential new avenue for treatment, particularly for patients who do not respond adequately to statins. However, concerns about long-term safety and cost remain significant barriers to widespread adoption.

==== Connection to depression ====
Inflammatory processes can be triggered by negative cognition or their consequences, such as stress, violence, or deprivation. Negative cognition may therefore contribute to inflammation, which in turn can lead to depression. A 2019 meta-analysis found that chronic inflammation is associated with a 30% increased risk of developing [[major depressive disorder]], supporting the link between inflammation and [[mental health]].<ref>{{cite journal | vauthors = Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD | title = Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls | journal = Brain, Behavior, and Immunity | volume = 87 | pages = 901–909 | date = July 2020 | pmid = 32113908 | pmc = 7327519 | doi = 10.1016/j.bbi.2020.02.010 }}</ref>

=== Allergy ===
An allergic reaction, formally known as [[Type I hypersensitivity|type 1 hypersensitivity]], is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is [[hay fever]], which is caused by a hypersensitive response by [[mast cell]]s to [[allergen]]s. Pre-sensitised mast cells respond by [[degranulation|degranulating]], releasing [[vasoactive]] chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes.<ref name="robspath" /> Severe inflammatory response may mature into a systemic response known as [[anaphylaxis]].

=== Myopathies ===
[[Inflammatory myopathy|Inflammatory myopathies]] are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as [[systemic sclerosis]], and include [[dermatomyositis]], [[polymyositis]], and [[inclusion body myositis]].<ref name="robspath" />

=== Leukocyte defects ===
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte functionality often result in a decreased capacity for inflammatory defense with subsequent vulnerability to infection.<ref name="robspath" /> Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria ([[Chédiak–Higashi syndrome]]), or produce [[microbicide]]s ([[chronic granulomatous disease]]). In addition, diseases affecting the [[bone marrow]] may result in abnormal or few leukocytes.

=== Pharmacological ===
Certain drugs or exogenous chemical compounds are known to affect inflammation. [[Vitamin A]] deficiency, for example, causes an increase in inflammatory responses,<ref>{{Cite journal |vauthors=Wiedermann U, Chen XJ, Enerbäck L, Hanson LA, Kahu H, Dahlgren UI |date=December 1996 |title=Vitamin A deficiency increases inflammatory responses |journal=Scandinavian Journal of Immunology |volume=44 |issue=6 |pages=578–84 |doi=10.1046/j.1365-3083.1996.d01-351.x |pmid=8972739 |s2cid=3079540}}</ref> and [[anti-inflammatory]] drugs work specifically by inhibiting the enzymes that produce inflammatory [[eicosanoids]]. Additionally, certain illicit drugs such as [[cocaine]] and [[Ecstasy (drug)|ecstasy]] may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. [[NF-κB]]).<ref>{{Cite journal |vauthors=Hargrave BY, Tiangco DA, Lattanzio FA, Beebe SJ |year=2003 |title=Cocaine, not morphine, causes the generation of reactive oxygen species and activation of NF-kappaB in transiently cotransfected heart cells |journal=Cardiovascular Toxicology |volume=3 |issue=2 |pages=141–51 |doi=10.1385/CT:3:2:141 |pmid=14501032 |s2cid=35240781}}</ref><ref>{{Cite journal |vauthors=Montiel-Duarte C, Ansorena E, López-Zabalza MJ, Cenarruzabeitia E, Iraburu MJ |date=March 2004 |title=Role of reactive oxygen species, glutathione and NF-kappaB in apoptosis induced by 3,4-methylenedioxymethamphetamine ("Ecstasy") on hepatic stellate cells |journal=Biochemical Pharmacology |volume=67 |issue=6 |pages=1025–33 |doi=10.1016/j.bcp.2003.10.020 |pmid=15006539}}</ref>

=== Cancer ===
Inflammation orchestrates the [[Tumor microenvironment|microenvironment]] around tumours, contributing to proliferation, survival and migration.<ref>{{Cite journal |vauthors=Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R |date=September 2011 |title=Interaction of tumor cells with the microenvironment |journal=Cell Communication and Signaling |volume=9 |pages=18 |doi=10.1186/1478-811X-9-18 |pmc=3180438 |pmid=21914164 |doi-access=free}}</ref> Cancer cells use [[selectins]], [[chemokines]] and their receptors for invasion, migration and metastasis.<ref name="Coussens" /> On the other hand, many cells of the immune system contribute to [[cancer immunology]], suppressing cancer.<ref name="pmid22914051">{{Cite journal |vauthors=Gunn L, Ding C, Liu M, Ma Y, Qi C, Cai Y, Hu X, Aggarwal D, Zhang HG, Yan J |date=September 2012 |title=Opposing roles for complement component C5a in tumor progression and the tumor microenvironment |journal=Journal of Immunology |volume=189 |issue=6 |pages=2985–94 |doi=10.4049/jimmunol.1200846 |pmc=3436956 |pmid=22914051}}</ref>
Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as [[NF-κB]], may mediate some of the most critical effects of inflammatory stimuli on cancer cells.<ref name="pmid19382224">{{Cite journal |vauthors=Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA |date=June 2009 |title=Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? |journal=BioEssays |volume=31 |issue=6 |pages=629–41 |doi=10.1002/bies.200800138 |pmid=19382224 |s2cid=205469320}}</ref> This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells is very likely to affect carcinogenesis. On the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.

There is some evidence from 2009 to suggest that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.<ref name="pmid19468060">{{Cite journal |vauthors=Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A |date=July 2009 |title=Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability |journal=Carcinogenesis |type=review |volume=30 |issue=7 |pages=1073–81 |doi=10.1093/carcin/bgp127 |pmid=19468060 |doi-access=free}}</ref>{{Update needed|date=October 2024}}

====Role in cancer====

In 1863, [[Rudolf Virchow]] hypothesized that the origin of cancer was at sites of chronic inflammation.<ref name="Coussens">{{Cite journal |vauthors=Coussens LM, Werb Z |year=2002 |title=Inflammation and cancer |journal=Nature |volume=420 |issue=6917 |pages=860–7 |bibcode=2002Natur.420..860C |doi=10.1038/nature01322 |pmc=2803035 |pmid=12490959}}</ref><ref name="Chiba">{{Cite journal |vauthors=Chiba T, Marusawa H, Ushijima T |date=September 2012 |title=Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation |url=http://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160134/1/j.gastro.2012.07.009.pdf |url-status=live |journal=Gastroenterology |volume=143 |issue=3 |pages=550–563 |doi=10.1053/j.gastro.2012.07.009 |pmid=22796521 |s2cid=206226588 |archive-url=https://web.archive.org/web/20220829232437/https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/160134/1/j.gastro.2012.07.009.pdf |archive-date=29 August 2022 |access-date=9 June 2018 |hdl-access=free |hdl=2433/160134}}</ref> As of 2012, chronic inflammation was estimated to contribute to approximately 15% to 25% of human cancers.<ref name="Chiba" /><ref name="pmid18650914">{{Cite journal |vauthors=Mantovani A, Allavena P, Sica A, Balkwill F |date=July 2008 |title=Cancer-related inflammation |url=https://air.unimi.it/bitstream/2434/145688/2/Cancer-related%20inflammation_Nature.pdf |url-status=live |journal=Nature |volume=454 |issue=7203 |pages=436–44 |bibcode=2008Natur.454..436M |doi=10.1038/nature07205 |pmid=18650914 |s2cid=4429118 |archive-url=https://web.archive.org/web/20221030195610/https://air.unimi.it/bitstream/2434/145688/2/Cancer-related%20inflammation_Nature.pdf |archive-date=30 October 2022 |access-date=9 June 2018 |hdl-access=free |hdl=2434/145688}}</ref>

====Mediators and DNA damage in cancer====

An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response.<ref name="pmid6399978">{{Cite journal |vauthors=Larsen GL, Henson PM |year=1983 |title=Mediators of inflammation |journal=Annual Review of Immunology |volume=1 |pages=335–59 |doi=10.1146/annurev.iy.01.040183.002003 |pmid=6399978}}</ref> Inflammatory mediators that contribute to neoplasia include [[prostaglandin]]s, inflammatory [[cytokine]]s such as [[Interleukin 1 beta|IL-1β]], [[tumor necrosis factor alpha|TNF-α]], [[Interleukin 6|IL-6]] and [[Interleukin 15|IL-15]] and [[chemokine]]s such as [[Interleukin 8|IL-8]] and [[CXCL1|GRO-alpha]].<ref name="Shacter">{{Cite journal |vauthors=Shacter E, Weitzman SA |date=February 2002 |title=Chronic inflammation and cancer |journal=Oncology |volume=16 |issue=2 |pages=217–26, 229; discussion 230–2 |pmid=11866137}}</ref><ref name="Chiba" /> These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival.<ref name="Coussens" /><ref name="Shacter" />

Inflammation also causes DNA damages due to the induction of [[reactive oxygen species]] (ROS) by various intracellular inflammatory mediators.<ref name="Coussens" /><ref name="Shacter" /><ref name="Chiba" /> In addition, [[White blood cell|leukocytes]] and other [[Phagocyte|phagocytic cells]] attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS and [[reactive nitrogen species]] (RNS). ROS and RNS are normally produced by these cells to fight infection.<ref name="Coussens" /> ROS, alone, cause more than 20 types of DNA damage.<ref name="pmid27989142">{{Cite journal |vauthors=Yu Y, Cui Y, Niedernhofer LJ, Wang Y |date=December 2016 |title=Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage |journal=Chemical Research in Toxicology |volume=29 |issue=12 |pages=2008–2039 |doi=10.1021/acs.chemrestox.6b00265 |pmc=5614522 |pmid=27989142}}</ref> Oxidative DNA damages cause both [[mutation]]s<ref name="pmid22293091">{{Cite journal |vauthors=Dizdaroglu M |date=December 2012 |title=Oxidatively induced DNA damage: mechanisms, repair and disease |journal=Cancer Letters |volume=327 |issue=1–2 |pages=26–47 |doi=10.1016/j.canlet.2012.01.016 |pmid=22293091}}</ref> and epigenetic alterations.<ref name="pmid24281019">{{Cite journal |vauthors=Nishida N, Kudo M |year=2013 |title=Oxidative stress and epigenetic instability in human hepatocarcinogenesis |journal=Digestive Diseases |volume=31 |issue=5–6 |pages=447–53 |doi=10.1159/000355243 |pmid=24281019 |doi-access=free}}</ref><ref name="Chiba" /><ref name="Ding">{{Cite journal |vauthors=Ding N, Maiuri AR, O'Hagan HM |year=2017 |title=The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases |journal=Mutation Research |volume=780 |pages=69–81 |doi=10.1016/j.mrrev.2017.09.005 |pmc=6690501 |pmid=31395351}}</ref> RNS also cause mutagenic DNA damages.<ref name="pmid28050219">{{Cite journal |vauthors=Kawanishi S, Ohnishi S, Ma N, Hiraku Y, Oikawa S, Murata M |year=2016 |title=Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells |journal=Genes and Environment |volume=38 |issue=1 |pages=26 |bibcode=2016GeneE..38...26K |doi=10.1186/s41021-016-0055-7 |pmc=5203929 |pmid=28050219 |doi-access=free}}</ref>

A normal cell may undergo [[carcinogenesis]] to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic [[mutation]]s due to [[DNA repair#Translecion synthesis|inaccurate repair]]. In addition, mistakes in the DNA repair process may cause [[Cancer epigenetics|epigenetic]] alterations.<ref name="Chiba" /><ref name="Shacter" /><ref name="Ding" /> Mutations and epigenetic alterations that are replicated and provide a selective advantage during somatic cell proliferation may be carcinogenic.

Genome-wide analyses of human cancer tissues reveal that a single typical cancer cell may possess roughly 100 mutations in [[coding region]]s, 10–20 of which are [[carcinogenesis|"driver mutations"]] that contribute to cancer development.<ref name="Chiba" /> However, chronic inflammation also causes epigenetic changes such as [[DNA methylation in cancer|DNA methylation]]s, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (see [[DNA methylation in cancer]]). Sites of oxidative damage in [[chromatin]] can recruit complexes that contain [[DNA methyltransferase]]s (DNMTs), a histone deacetylase ([[sirtuin 1|SIRT1]]), and a [[EZH2|histone methyltransferase (EZH2)]], and thus induce DNA methylation.<ref name="Chiba" /><ref name="pmid22094255">{{Cite journal |vauthors=O'Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL, Baylin SB |date=November 2011 |title=Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands |journal=Cancer Cell |volume=20 |issue=5 |pages=606–19 |doi=10.1016/j.ccr.2011.09.012 |pmc=3220885 |pmid=22094255}}</ref><ref name="pmid28522752">{{Cite journal |vauthors=Maiuri AR, Peng M, Podicheti R, Sriramkumar S, Kamplain CM, Rusch DB, DeStefano Shields CE, Sears CL, O'Hagan HM |date=July 2017 |title=Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis |journal=Cancer Research |volume=77 |issue=13 |pages=3467–3478 |doi=10.1158/0008-5472.CAN-17-0056 |pmc=5516887 |pmid=28522752}}</ref> DNA methylation of a [[CpG site|CpG island]] in a [[Promoter (genetics)|promoter region]] may cause silencing of its downstream gene (see [[CpG site]] and [[regulation of transcription in cancer]]). DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (see [[DNA methylation in cancer#Likely role of hypermethylation of DNA repair genes in cancer|hypermethylation of DNA repair genes in cancer]]). A 2018 report<ref name="pmid29358395">{{Cite journal |vauthors=Yamashita S, Kishino T, Takahashi T, Shimazu T, Charvat H, Kakugawa Y, Nakajima T, Lee YC, Iida N, Maeda M, Hattori N, Takeshima H, Nagano R, Oda I, Tsugane S, Wu MS, Ushijima T |date=February 2018 |title=Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=115 |issue=6 |pages=1328–1333 |bibcode=2018PNAS..115.1328Y |doi=10.1073/pnas.1717340115 |pmc=5819434 |pmid=29358395 |doi-access=free}}</ref> evaluated the relative importance of mutations and epigenetic alterations in progression to two different types of cancer. This report showed that epigenetic alterations were much more important than mutations in generating gastric cancers (associated with inflammation).<ref name="pmid24664859">{{Cite journal |vauthors=Raza Y, Khan A, Farooqui A, Mubarak M, Facista A, Akhtar SS, Khan S, Kazi JI, Bernstein C, Kazmi SU |date=October 2014 |title=Oxidative DNA damage as a potential early biomarker of Helicobacter pylori associated carcinogenesis |journal=Pathology & Oncology Research |volume=20 |issue=4 |pages=839–46 |doi=10.1007/s12253-014-9762-1 |pmid=24664859 |s2cid=18727504}}</ref> However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated with [[Cigarette#Smokers|tobacco chemicals]] and [[Acetaldehyde#Carcinogenicity|acetaldehyde]], a product of alcohol metabolism).

=== HIV and AIDS ===

It has long been recognized that infection with [[HIV]] is characterized not only by development of profound [[immunodeficiency]] but also by sustained inflammation and immune activation.<ref name="Deeks 141–155">{{Cite journal |vauthors=Deeks SG |date=2011-01-01 |title=HIV infection, inflammation, immunosenescence, and aging |journal=Annual Review of Medicine |volume=62 |pages=141–55 |doi=10.1146/annurev-med-042909-093756 |pmc=3759035 |pmid=21090961}}</ref><ref>{{Cite journal |vauthors=Klatt NR, Chomont N, Douek DC, Deeks SG |date=July 2013 |title=Immune activation and HIV persistence: implications for curative approaches to HIV infection |journal=Immunological Reviews |volume=254 |issue=1 |pages=326–42 |doi=10.1111/imr.12065 |pmc=3694608 |pmid=23772629}}</ref><ref>{{Cite journal |vauthors=Salazar-Gonzalez JF, Martinez-Maza O, Nishanian P, Aziz N, Shen LP, Grosser S, Taylor J, Detels R, Fahey JL |date=August 1998 |title=Increased immune activation precedes the inflection point of CD4 T cells and the increased serum virus load in human immunodeficiency virus infection |journal=The Journal of Infectious Diseases |volume=178 |issue=2 |pages=423–30 |doi=10.1086/515629 |pmid=9697722 |doi-access=free}}</ref> A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency.<ref name="Deeks 141–155" /><ref>{{Cite journal |vauthors=Ipp H, Zemlin A |date=February 2013 |title=The paradox of the immune response in HIV infection: when inflammation becomes harmful |journal=Clinica Chimica Acta; International Journal of Clinical Chemistry |volume=416 |pages=96–9 |doi=10.1016/j.cca.2012.11.025 |pmid=23228847}}</ref> Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease.<ref>{{Cite journal |vauthors=Nasi M, Pinti M, Mussini C, Cossarizza A |date=October 2014 |title=Persistent inflammation in HIV infection: established concepts, new perspectives |journal=Immunology Letters |volume=161 |issue=2 |pages=184–8 |doi=10.1016/j.imlet.2014.01.008 |pmid=24487059}}</ref> Even after the introduction of [[Antiretroviral therapy, highly active|effective antiretroviral therapy]] (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency: [[Simian immunodeficiency virus|SIV]]<nowiki/>sm infection of its natural nonhuman primate hosts, the [[sooty mangabey]], causes high-level viral replication but limited evidence of disease.<ref>{{Cite journal |vauthors=Milush JM, Mir KD, Sundaravaradan V, Gordon SN, Engram J, Cano CA, Reeves JD, Anton E, O'Neill E, Butler E, Hancock K, Cole KS, Brenchley JM, Else JG, Silvestri G, Sodora DL |date=March 2011 |title=Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells |journal=The Journal of Clinical Investigation |volume=121 |issue=3 |pages=1102–10 |doi=10.1172/JCI44876 |pmc=3049370 |pmid=21317533}}</ref><ref>{{Cite journal |vauthors=Rey-Cuillé MA, Berthier JL, Bomsel-Demontoy MC, Chaduc Y, Montagnier L, Hovanessian AG, Chakrabarti LA |date=May 1998 |title=Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease |journal=Journal of Virology |volume=72 |issue=5 |pages=3872–86 |doi=10.1128/JVI.72.5.3872-3886.1998 |pmc=109612 |pmid=9557672}}</ref> This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental [[Simian immunodeficiency virus|SIV]]<nowiki/>sm infection of [[rhesus macaque]] produces immune activation and AIDS-like disease with many parallels to human HIV infection.<ref>{{Cite journal |vauthors=Chahroudi A, Bosinger SE, Vanderford TH, Paiardini M, Silvestri G |date=March 2012 |title=Natural SIV hosts: showing AIDS the door |journal=Science |volume=335 |issue=6073 |pages=1188–93 |bibcode=2012Sci...335.1188C |doi=10.1126/science.1217550 |pmc=3822437 |pmid=22403383}}</ref>

Delineating how [[CD4]] T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis{{emdash}}one of the top priorities for HIV research by the Office of AIDS Research, [[National Institute of Allergy and Infectious Diseases|National Institutes of Health]]. Recent studies demonstrated that [[Caspase 1|caspase-1]]-mediated [[pyroptosis]], a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV.<ref name="Doitsh 509–514">{{Cite journal |vauthors=Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC |date=January 2014 |title=Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection |journal=Nature |volume=505 |issue=7484 |pages=509–14 |bibcode=2014Natur.505..509D |doi=10.1038/nature12940 |pmc=4047036 |pmid=24356306}}</ref><ref>{{Cite journal |vauthors=Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC |date=January 2014 |title=IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV |journal=Science |volume=343 |issue=6169 |pages=428–32 |bibcode=2014Sci...343..428M |doi=10.1126/science.1243640 |pmc=3976200 |pmid=24356113}}</ref><ref>{{Cite journal |vauthors=Galloway NL, Doitsh G, Monroe KM, Yang Z, Muñoz-Arias I, Levy DN, Greene WC |date=September 2015 |title=Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells |journal=Cell Reports |volume=12 |issue=10 |pages=1555–1563 |doi=10.1016/j.celrep.2015.08.011 |pmc=4565731 |pmid=26321639}}</ref> These are the two signature events that propel HIV disease progression to [[HIV/AIDS|AIDS]]. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die. The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury.<ref>{{Cite journal |vauthors=Doitsh G, Greene WC |date=March 2016 |title=Dissecting How CD4 T Cells Are Lost During HIV Infection |journal=Cell Host & Microbe |volume=19 |issue=3 |pages=280–91 |doi=10.1016/j.chom.2016.02.012 |pmc=4835240 |pmid=26962940}}</ref> Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflammatory cytokines such as [[Interleukin 1 beta|IL-1β]] and [[Interleukin 18|IL-18]] can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765,<ref name="Doitsh 509–514" /> which has already proven to be safe and well tolerated in phase II human clinical trials.<ref>{{Cite journal |date=19 December 2013 |title=Study of VX-765 in Subjects With Treatment-resistant Partial Epilepsy – Full Text View – ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT01048255 |url-status=live |archive-url=https://web.archive.org/web/20220926164557/https://clinicaltrials.gov/ct2/show/NCT01048255 |archive-date=26 September 2022 |access-date=2016-05-21 |website=clinicaltrials.gov}}</ref> These findings could propel development of an entirely new class of "anti-AIDS" therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting "tolerance" of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation.

=== Resolution ===
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.<ref name="robspath" /> Failure to do so results in chronic inflammation, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues.
Mechanisms that serve to terminate inflammation include:<ref name="robspath" /><ref>{{Cite journal |vauthors=Eming SA, Krieg T, Davidson JM |date=March 2007 |title=Inflammation in wound repair: molecular and cellular mechanisms |journal=The Journal of Investigative Dermatology |volume=127 |issue=3 |pages=514–25 |doi=10.1038/sj.jid.5700701 |pmid=17299434 |doi-access=free}}</ref>

{{columns-list|colwidth=30em|
* Short [[half-life]] of [[inflammatory mediators]] ''in vivo''.
* Production and release of [[transforming growth factor (TGF) beta]] from [[macrophages]]<ref>{{Cite journal |vauthors=Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB |date=September 1999 |title=Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response |journal=Nature Cell Biology |volume=1 |issue=5 |pages=260–6 |doi=10.1038/12971 |pmid=10559937 |s2cid=37216623}}</ref><ref>{{Cite journal |vauthors=Ashcroft GS |date=December 1999 |title=Bidirectional regulation of macrophage function by TGF-beta |url=https://zenodo.org/record/1260212 |url-status=live |journal=Microbes and Infection |volume=1 |issue=15 |pages=1275–82 |doi=10.1016/S1286-4579(99)00257-9 |pmid=10611755 |archive-url=https://web.archive.org/web/20200110215702/https://zenodo.org/record/1260212 |archive-date=10 January 2020 |access-date=11 September 2019}}</ref><ref>{{Cite journal |vauthors=Werner F, Jain MK, Feinberg MW, Sibinga NE, Pellacani A, Wiesel P, Chin MT, Topper JN, Perrella MA, Lee ME |date=November 2000 |title=Transforming growth factor-beta 1 inhibition of macrophage activation is mediated via Smad3 |journal=The Journal of Biological Chemistry |volume=275 |issue=47 |pages=36653–8 |doi=10.1074/jbc.M004536200 |pmid=10973958 |doi-access=free}}</ref>
* Production and release of [[interleukin 10]] (IL-10)<ref>{{Cite journal |vauthors=Sato Y, Ohshima T, Kondo T |date=November 1999 |title=Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing |journal=Biochemical and Biophysical Research Communications |volume=265 |issue=1 |pages=194–9 |doi=10.1006/bbrc.1999.1455 |pmid=10548513}}</ref>
* Production of anti-inflammatory [[specialized proresolving mediators]], i.e. [[lipoxin]]s, [[resolvin]]s, [[maresin]]s, and [[neuroprotectin]]s<ref>{{Cite journal |vauthors=Serhan CN |date=August 2008 |title=Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators |journal=Journal of Periodontology |volume=79 |issue=8 Suppl |pages=1520–6 |doi=10.1902/jop.2008.080231 |pmid=18673006}}</ref><ref name="pmid25911383">{{Cite journal |vauthors=Headland SE, Norling LV |date=May 2015 |title=The resolution of inflammation: Principles and challenges |journal=Seminars in Immunology |volume=27 |issue=3 |pages=149–60 |doi=10.1016/j.smim.2015.03.014 |pmid=25911383}}</ref>
* Downregulation of pro-inflammatory molecules, such as [[leukotrienes]].
* Upregulation of anti-inflammatory molecules such as the [[interleukin 1 receptor antagonist]] or the soluble [[tumor necrosis factor receptor]] (TNFR)
* [[Apoptosis]] of pro-inflammatory cells<ref>{{Cite journal |vauthors=Greenhalgh DG |date=September 1998 |title=The role of apoptosis in wound healing |journal=The International Journal of Biochemistry & Cell Biology |volume=30 |issue=9 |pages=1019–30 |doi=10.1016/S1357-2725(98)00058-2 |pmid=9785465}}</ref>
* Desensitization of receptors.
* Increased survival of cells in regions of inflammation due to their interaction with the [[extracellular matrix]] (ECM)<ref>{{Cite journal |vauthors=Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW |date=November 2005 |title=Regulation of lung injury and repair by Toll-like receptors and hyaluronan |journal=Nature Medicine |volume=11 |issue=11 |pages=1173–9 |doi=10.1038/nm1315 |pmid=16244651 |s2cid=11765495}}</ref><ref>{{Cite journal |vauthors=Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Puré E, Henson PM, Noble PW |date=April 2002 |title=Resolution of lung inflammation by CD44 |journal=Science |volume=296 |issue=5565 |pages=155–8 |bibcode=2002Sci...296..155T |doi=10.1126/science.1069659 |pmid=11935029 |s2cid=7905603}}</ref>
* Downregulation of receptor activity by high concentrations of [[ligands]]
* Cleavage of [[chemokine]]s by [[matrix metalloproteinases]] (MMPs) might lead to production of anti-inflammatory factors.<ref>{{Cite journal |vauthors=McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I, Overall CM |date=August 2000 |title=Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 |journal=Science |volume=289 |issue=5482 |pages=1202–6 |bibcode=2000Sci...289.1202M |doi=10.1126/science.289.5482.1202 |pmid=10947989}}</ref>
}}
{{Cquote|Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, [[granulocyte]]s promote the switch of [[arachidonic acid]]–derived [[prostaglandin]]s and [[leukotriene]]s to lipoxins, which initiate the termination sequence. [[Neutrophil]] recruitment thus ceases and programmed death by [[apoptosis]] is engaged. These events coincide with the biosynthesis, from [[omega-3 fatty acid|omega-3 polyunsaturated fatty acids]], of [[resolvins]] and [[Neuroprotectin|protectins]], which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergo [[phagocytosis]] by [[macrophage]]s, leading to neutrophil clearance and release of anti-inflammatory and reparative [[cytokines]] such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through the [[Lymphatic system|lymphatics]].<ref name="pmid16369558">{{Cite journal |vauthors=Serhan CN, Savill J |date=December 2005 |title=Resolution of inflammation: the beginning programs the end |journal=Nature Immunology |volume=6 |issue=12 |pages=1191–7 |doi=10.1038/ni1276 |pmid=16369558 |s2cid=22379843}}</ref>|30px|30px|[[Charles N. Serhan]]
}}

=== Connection to depression ===
There is evidence for a link between [[Depression and immune function#Depression and inflammation|inflammation and depression]].<ref>{{Cite journal |vauthors=Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, Maes M |date=September 2013 |title=So depression is an inflammatory disease, but where does the inflammation come from? |journal=BMC Medicine |volume=11 |pages=200 |doi=10.1186/1741-7015-11-200 |pmc=3846682 |pmid=24228900 |doi-access=free}}</ref> Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.<ref name="Cox et al. (2012)">{{Cite journal |vauthors=Cox WT, Abramson LY, Devine PG, Hollon SD |date=September 2012 |title=Stereotypes, Prejudice, and Depression: The Integrated Perspective |journal=Perspectives on Psychological Science |volume=7 |issue=5 |pages=427–49 |doi=10.1177/1745691612455204 |pmid=26168502 |s2cid=1512121}}</ref><ref>{{Cite journal |vauthors=Kiecolt-Glaser JK, Derry HM, Fagundes CP |date=November 2015 |title=Inflammation: depression fans the flames and feasts on the heat |journal=The American Journal of Psychiatry |volume=172 |issue=11 |pages=1075–91 |doi=10.1176/appi.ajp.2015.15020152 |pmc=6511978 |pmid=26357876}}</ref>{{Dubious|Depression|reason=Implausible claim apparently not supported by citation.|date=July 2013}}
In addition, there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode".<ref>{{Cite news |date=2015-01-04 |title=Is depression a kind of allergic reaction? |url=https://www.theguardian.com/lifeandstyle/2015/jan/04/depression-allergic-reaction-inflammation-immune-system |url-status=live |archive-url=https://web.archive.org/web/20221021202426/https://www.theguardian.com/lifeandstyle/2015/jan/04/depression-allergic-reaction-inflammation-immune-system |archive-date=21 October 2022 |access-date=11 December 2016 |work=The Guardian |vauthors=Williams C}}</ref>

Classical symptoms of being physically sick, such as lethargy, show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during the depressive episodes of people with bipolar disorder and drop off during remission.<ref>{{Cite journal |vauthors=Brietzke E, Stertz L, Fernandes BS, Kauer-Sant'anna M, Mascarenhas M, Escosteguy Vargas A, Chies JA, Kapczinski F |date=August 2009 |title=Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder |journal=Journal of Affective Disorders |volume=116 |issue=3 |pages=214–7 |doi=10.1016/j.jad.2008.12.001 |pmid=19251324}}</ref> Furthermore, it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion of subjects positively responding to treatment.<ref>{{Cite journal |vauthors=Müller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Möller HJ, Arolt V, Riedel M |date=July 2006 |title=The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine |journal=Molecular Psychiatry |volume=11 |issue=7 |pages=680–4 |doi=10.1038/sj.mp.4001805 |pmid=16491133 |doi-access=free}}</ref>
Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.<ref>{{Cite journal |vauthors=Canli T |year=2014 |title=Reconceptualizing major depressive disorder as an infectious disease |journal=Biology of Mood & Anxiety Disorders |volume=4 |pages=10 |doi=10.1186/2045-5380-4-10 |pmc=4215336 |pmid=25364500 |doi-access=free}}</ref>

=== Connection to delirium ===
There is evidence for a link between inflammation and [[delirium]] based on the results of a recent longitudinal study investigating CRP in COVID-19 patients.<ref>{{Cite journal |vauthors=Saini A, Oh TH, Ghanem DA, Castro M, Butler M, Sin Fai Lam CC, Posporelis S, Lewis G, David AS, Rogers JP |date=October 2022 |title=Inflammatory and blood gas markers of COVID-19 delirium compared to non-COVID-19 delirium: a cross-sectional study |url=https://discovery.ucl.ac.uk/id/eprint/10136824/ |url-status=live |journal=Aging & Mental Health |volume=26 |issue=10 |pages=2054–2061 |doi=10.1080/13607863.2021.1989375 |pmid=34651536 |s2cid=238990849 |archive-url=https://web.archive.org/web/20211022093940/https://discovery.ucl.ac.uk/id/eprint/10136824/ |archive-date=22 October 2021 |access-date=20 February 2023 |doi-access=free}}</ref>