Editing Macrophage (section)

== Clinical significance ==
Due to their role in phagocytosis, macrophages are involved in many diseases of the immune system. For example, they participate in the formation of [[granuloma]]s, inflammatory lesions that may be caused by a large number of diseases. Some disorders, mostly rare, of ineffective phagocytosis and macrophage function have been described, for example.<ref>{{cite book | vauthors = Wolf AJ, Underhill DM |title=Macrophages: Biology and Role in the Pathology of Diseases|chapter=Phagocytosis|date=2014|pages=91–109|publisher=Springer New York|doi=10.1007/978-1-4939-1311-4_5|isbn=978-1-4939-1310-7}}</ref>

=== As a host for intracellular pathogens ===
In their role as a phagocytic immune cell macrophages are responsible for engulfing pathogens to destroy them. Some pathogens subvert this process and instead live inside the macrophage. This provides an environment in which the pathogen is hidden from the immune system and allows it to replicate.{{citation needed|date=March 2023}}

Diseases with this type of behaviour include [[tuberculosis]] (caused by ''[[Mycobacterium tuberculosis]]'') and [[leishmaniasis]] (caused by ''[[Leishmania]]'' species).{{citation needed|date=March 2023}}

In order to minimize the possibility of becoming the host of an intracellular bacteria, macrophages have evolved defense mechanisms such as induction of nitric oxide and reactive oxygen intermediates,<ref>{{cite journal | vauthors = Herb M, Schramm M | title = Functions of ROS in Macrophages and Antimicrobial Immunity | journal = Antioxidants | volume = 10 | issue = 2 | page = 313 | date = February 2021 | pmid = 33669824 | pmc = 7923022 | doi = 10.3390/antiox10020313 | doi-access = free }}</ref> which are toxic to microbes. Macrophages have also evolved the ability to restrict the microbe's nutrient supply and induce [[autophagy]].<ref>{{cite journal | vauthors = Weiss G, Schaible UE | title = Macrophage defense mechanisms against intracellular bacteria | journal = Immunological Reviews | volume = 264 | issue = 1 | pages = 182–203 | date = March 2015 | pmid = 25703560 | pmc = 4368383 | doi = 10.1111/imr.12266 }}</ref>

==== Tuberculosis ====
Once engulfed by a macrophage, the causative agent of tuberculosis, ''Mycobacterium tuberculosis'',<ref name="Sherris">{{cite book|title=Sherris Medical Microbiology|publisher=McGraw Hill|year=2004|isbn=978-0-8385-8529-0|veditors=Ryan KJ, Ray CG|edition=4th}}</ref> avoids cellular defenses and uses the cell to replicate. Recent evidence suggests that in response to the pulmonary infection of ''Mycobacterium tuberculosis'', the peripheral macrophages matures into M1 phenotype. Macrophage M1 phenotype is characterized by increased secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and increased glycolytic activities essential for clearance of infection.<ref name="NIX-mediated mitophagy regulate met"/>

==== Leishmaniasis ====
Upon phagocytosis by a macrophage, the ''Leishmania'' parasite finds itself in a phagocytic vacuole. Under normal circumstances, this phagocytic vacuole would develop into a lysosome and its contents would be digested. ''Leishmania'' alter this process and avoid being destroyed; instead, they make a home inside the vacuole.{{citation needed|date=March 2023}}

==== Chikungunya ====
Infection of macrophages in joints is associated with local inflammation during and after the acute phase of ''[[Chikungunya]]'' (caused by CHIKV or Chikungunya virus).<ref name="CHIKV persistence in human body">{{cite journal | vauthors = Dupuis-Maguiraga L, Noret M, Brun S, Le Grand R, Gras G, Roques P | title = Chikungunya disease: infection-associated markers from the acute to the chronic phase of arbovirus-induced arthralgia | journal = PLOS Neglected Tropical Diseases | volume = 6 | issue = 3 | pages = e1446 | year = 2012 | pmid = 22479654 | pmc = 3313943 | doi = 10.1371/journal.pntd.0001446 | doi-access = free }}</ref>

==== Others ====
[[Adenovirus]] (most common cause of pink eye) can remain latent in a host macrophage, with continued viral shedding 6–18 months after initial infection.{{citation needed|date=March 2023}}

''Brucella spp.'' can remain latent in a macrophage via inhibition of [[phagosome]]–[[lysosome]] fusion; causes [[brucellosis]] (undulant fever).{{citation needed|date=March 2023}}

''[[Legionella pneumophila]]'', the causative agent of [[Legionnaires' disease]], also establishes residence within macrophages.{{citation needed|date=March 2023}}

=== Heart disease ===
Macrophages are the predominant cells involved in creating the progressive plaque lesions of [[atherosclerosis]].<ref>{{cite journal | vauthors = Lucas AD, Greaves DR | title = Atherosclerosis: role of chemokines and macrophages | journal = Expert Reviews in Molecular Medicine | volume = 3 | issue = 25 | pages = 1–18 | date = November 2001 | pmid = 14585150 | doi = 10.1017/S1462399401003696 | s2cid = 8952545 }}</ref>

Focal recruitment of macrophages occurs after the onset of acute [[myocardial infarction]]. These macrophages function to remove debris, apoptotic cells and to prepare for [[Regeneration (biology)|tissue regeneration]].<ref>{{cite journal | vauthors = Frantz S, Nahrendorf M | title = Cardiac macrophages and their role in ischaemic heart disease | journal = Cardiovascular Research | volume = 102 | issue = 2 | pages = 240–248 | date = May 2014 | pmid = 24501331 | pmc = 3989449 | doi = 10.1093/cvr/cvu025 }}</ref> Macrophages protect against ischemia-induced ventricular tachycardia in hypokalemic mice.<ref>{{cite journal | vauthors = Grune J, Lewis AJ, Yamazoe M, Hulsmans M, Rohde D, Xiao L, Zhang S, Ott C, Calcagno DM, Zhou Y, Timm K, Shanmuganathan M, Pulous FE, Schloss MJ, Foy BH, Capen D, Vinegoni C, Wojtkiewicz GR, Iwamoto Y, Grune T, Brown D, Higgins J, Ferreira VM, Herring N, Channon KM, Neubauer S, Sosnovik DE, Milan DJ, Swirski FK, King KR, Aguirre AD, Ellinor PT, Nahrendorf M | title = Neutrophils incite and macrophages avert electrical storm after myocardial infarction | journal = Nature Cardiovascular Research | volume = 1 | issue = 7 | pages = 649–664 | date = July 2022 | pmid = 36034743 | pmc = 9410341 | doi = 10.1038/s44161-022-00094-w | s2cid = 250475623 }}</ref>

=== HIV infection ===
Macrophages also play a role in [[human Immunodeficiency Virus|human immunodeficiency virus]] (HIV) infection. Like [[T cells]], macrophages can be infected with HIV, and even become a reservoir of ongoing virus replication throughout the body. HIV can enter the macrophage through binding of gp120 to CD4 and second membrane receptor, CCR5 (a chemokine receptor). Both circulating monocytes and macrophages serve as a reservoir for the virus.<ref>{{cite journal| vauthors = Bol SM, Cobos-Jiménez V, Kootstra NA, van't Wout AB |date=February 2011|title=Macrophage |journal=Future Virology|volume=6|issue=2|pages=187–208|doi=10.2217/fvl.10.93}}</ref> Macrophages are better able to resist infection by HIV-1 than CD4+ T cells, although susceptibility to HIV infection differs among macrophage subtypes.<ref>{{cite journal | vauthors = Koppensteiner H, Brack-Werner R, Schindler M | title = Macrophages and their relevance in Human Immunodeficiency Virus Type I infection | journal = Retrovirology | volume = 9 | issue = 1 | pages = 82 | date = October 2012 | pmid = 23035819 | pmc = 3484033 | doi = 10.1186/1742-4690-9-82 | doi-access = free }}</ref>

=== Cancer ===
Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells.<ref>{{cite journal | vauthors = Qian BZ, Pollard JW | title = Macrophage diversity enhances tumor progression and metastasis | journal = Cell | volume = 141 | issue = 1 | pages = 39–51 | date = April 2010 | pmid = 20371344 | pmc = 4994190 | doi = 10.1016/j.cell.2010.03.014 }}</ref><ref name="nature.com">{{cite journal | vauthors = Engblom C, Pfirschke C, Pittet MJ | title = The role of myeloid cells in cancer therapies | journal = Nature Reviews. Cancer | volume = 16 | issue = 7 | pages = 447–462 | date = July 2016 | pmid = 27339708 | doi = 10.1038/nrc.2016.54 | s2cid = 21924175 }}</ref> Inflammatory compounds, such as [[tumor necrosis factor]] (TNF)-alpha released by the macrophages activate the gene switch [[NF-κB|nuclear factor-kappa B]]. NF-κB then enters the nucleus of a tumor cell and turns on production of proteins that stop [[apoptosis]] and promote cell proliferation and inflammation.<ref>{{cite journal | vauthors = Stix G | title = A malignant flame. Understanding chronic inflammation, which contributes to heart disease, Alzheimer's and a variety of other ailments, may be a key to unlocking the mysteries of cancer | journal = Scientific American | volume = 297 | issue = 1 | pages = 60–67 | date = July 2007 | pmid = 17695843 | doi = 10.1038/scientificamerican0707-60 | bibcode = 2007SciAm.297a..60S }}</ref> Moreover, macrophages serve as a source for many pro-angiogenic factors including [[Vascular endothelial growth factor|vascular endothelial factor]] (VEGF), [[tumor necrosis factor-alpha]] (TNF-alpha), [[macrophage colony-stimulating factor]] (M-CSF/CSF1) and [[Interleukin 1|IL-1]] and [[Interleukin 6|IL-6]],<ref>{{cite journal | vauthors = Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW | title = Macrophages regulate the angiogenic switch in a mouse model of breast cancer | journal = Cancer Research | volume = 66 | issue = 23 | pages = 11238–11246 | date = December 2006 | pmid = 17114237 | doi = 10.1158/0008-5472.can-06-1278 | s2cid = 12722658 | doi-access =  }}</ref> contributing further to the tumor growth. 

Macrophages have been shown to infiltrate a number of tumors. Their number correlates with poor prognosis in certain cancers, including cancers of breast, cervix, bladder, brain and prostate.<ref>Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002; 196:254–65.</ref><ref>{{Cite journal| vauthors = de Groot AE |date=July 2018|title=In vitro human tumor-associated macrophage model implicates macrophage proliferation as a mechanism for maintaining tumor-associated macrophage populations|url=http://cancerres.aacrjournals.org/content/78/13_Supplement/4060.short|journal=Cancer Research|volume=78|issue=13 Supplement|pages=4060|doi=10.1158/1538-7445.AM2018-4060|s2cid=80769044 |doi-access=}}</ref> Some tumors can also produce factors, including M-CSF/CSF1, [[CCL2|MCP-1/CCL2]] and [[Angiotensin II]], that trigger the amplification and mobilization of macrophages in tumors.<ref>{{cite journal | vauthors = Lin EY, Nguyen AV, Russell RG, Pollard JW | title = Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy | journal = The Journal of Experimental Medicine | volume = 193 | issue = 6 | pages = 727–740 | date = March 2001 | pmid = 11257139 | pmc = 2193412 | doi = 10.1084/jem.193.6.727 }}</ref><ref>{{cite journal | vauthors = Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW | title = CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis | journal = Nature | volume = 475 | issue = 7355 | pages = 222–225 | date = June 2011 | pmid = 21654748 | pmc = 3208506 | doi = 10.1038/nature10138 }}</ref><ref>{{cite journal | vauthors = Cortez-Retamozo V, Etzrodt M, Newton A, Ryan R, Pucci F, Sio SW, Kuswanto W, Rauch PJ, Chudnovskiy A, Iwamoto Y, Kohler R, Marinelli B, Gorbatov R, Wojtkiewicz G, Panizzi P, Mino-Kenudson M, Forghani R, Figueiredo JL, Chen JW, Xavier R, Swirski FK, Nahrendorf M, Weissleder R, Pittet MJ | title = Angiotensin II drives the production of tumor-promoting macrophages | journal = Immunity | volume = 38 | issue = 2 | pages = 296–308 | date = February 2013 | pmid = 23333075 | pmc = 3582771 | doi = 10.1016/j.immuni.2012.10.015 }}</ref> Additionally, subcapsular sinus macrophages in tumor-draining lymph nodes can suppress cancer progression by containing the spread of tumor-derived materials.<ref>{{cite journal | vauthors = Pucci F, Garris C, Lai CP, Newton A, Pfirschke C, Engblom C, Alvarez D, Sprachman M, Evavold C, Magnuson A, von Andrian UH, Glatz K, Breakefield XO, Mempel TR, Weissleder R, Pittet MJ | title = SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions | journal = Science | volume = 352 | issue = 6282 | pages = 242–246 | date = April 2016 | pmid = 26989197 | pmc = 4960636 | doi = 10.1126/science.aaf1328 | bibcode = 2016Sci...352..242P }}</ref>

=== Cancer therapy ===
Experimental studies indicate that macrophages can affect all therapeutic modalities, including [[surgery]], [[chemotherapy]], [[radiotherapy]], [[immunotherapy]] and [[targeted therapy]].<ref name="nature.com" /><ref>{{cite journal | vauthors = Mantovani A, Allavena P | title = The interaction of anticancer therapies with tumor-associated macrophages | journal = The Journal of Experimental Medicine | volume = 212 | issue = 4 | pages = 435–445 | date = April 2015 | pmid = 25753580 | pmc = 4387285 | doi = 10.1084/jem.20150295 }}</ref><ref>{{cite journal | vauthors = De Palma M, Lewis CE | title = Macrophage regulation of tumor responses to anticancer therapies | journal = Cancer Cell | volume = 23 | issue = 3 | pages = 277–286 | date = March 2013 | pmid = 23518347 | doi = 10.1016/j.ccr.2013.02.013 | doi-access = free }}</ref> Macrophages can influence treatment outcomes both positively and negatively. Macrophages can be protective in different ways: they can remove dead tumor cells (in a process called [[phagocytosis]]) following treatments that kill these cells; they can serve as drug depots for some anticancer drugs;<ref>{{cite journal | vauthors = Miller MA, Zheng YR, Gadde S, Pfirschke C, Zope H, Engblom C, Kohler RH, Iwamoto Y, Yang KS, Askevold B, Kolishetti N, Pittet M, Lippard SJ, Farokhzad OC, Weissleder R | title = Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug | journal = Nature Communications | volume = 6 | pages = 8692 | date = October 2015 | pmid = 26503691 | pmc = 4711745 | doi = 10.1038/ncomms9692 | bibcode = 2015NatCo...6.8692M }}</ref> they can also be activated by some therapies to promote antitumor immunity.<ref>{{cite journal | vauthors = Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schäkel K, Garbi N, Jäger D, Weitz J, Schmitz-Winnenthal H, Hämmerling GJ, Beckhove P | title = Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy | journal = Cancer Cell | volume = 24 | issue = 5 | pages = 589–602 | date = November 2013 | pmid = 24209604 | doi = 10.1016/j.ccr.2013.09.014 | doi-access = free }}</ref> Macrophages can also be deleterious in several ways: for example they can suppress various chemotherapies,<ref>{{cite journal | vauthors = Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, Daniel D, Hwang ES, Rugo HS, Coussens LM | title = Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells | journal = Cancer Cell | volume = 26 | issue = 5 | pages = 623–637 | date = November 2014 | pmid = 25446896 | pmc = 4254570 | doi = 10.1016/j.ccell.2014.09.006 }}</ref><ref>{{cite journal | vauthors = DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirström K, West BL, Coussens LM | title = Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy | journal = Cancer Discovery | volume = 1 | issue = 1 | pages = 54–67 | date = June 2011 | pmid = 22039576 | pmc = 3203524 | doi = 10.1158/2159-8274.CD-10-0028 }}</ref> radiotherapies<ref>{{cite journal | vauthors = Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM | title = TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy | journal = Cancer Immunology Research | volume = 3 | issue = 5 | pages = 518–525 | date = May 2015 | pmid = 25716473 | pmc = 4420686 | doi = 10.1158/2326-6066.CIR-14-0232 }}</ref><ref>{{cite journal | vauthors = Kozin SV, Kamoun WS, Huang Y, Dawson MR, Jain RK, Duda DG | title = Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation | journal = Cancer Research | volume = 70 | issue = 14 | pages = 5679–5685 | date = July 2010 | pmid = 20631066 | pmc = 2918387 | doi = 10.1158/0008-5472.CAN-09-4446 }}</ref> and immunotherapies.<ref>{{cite journal | vauthors = Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM, Weissleder R, Pittet MJ | title = In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy | journal = Science Translational Medicine | volume = 9 | issue = 389 | pages = eaal3604 | date = May 2017 | pmid = 28490665 | pmc = 5734617 | doi = 10.1126/scitranslmed.aal3604 }}</ref><ref>{{cite journal | vauthors = Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG | title = CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models | journal = Cancer Research | volume = 74 | issue = 18 | pages = 5057–5069 | date = September 2014 | pmid = 25082815 | pmc = 4182950 | doi = 10.1158/0008-5472.CAN-13-3723 }}</ref> Because macrophages can regulate tumor progression, therapeutic strategies to reduce the number of these cells, or to manipulate their phenotypes, are currently being tested in cancer patients.<ref>{{cite journal | vauthors = Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, Jones T, Jucknischke U, Scheiblich S, Kaluza K, Gorr IH, Walz A, Abiraj K, Cassier PA, Sica A, Gomez-Roca C, de Visser KE, Italiano A, Le Tourneau C, Delord JP, Levitsky H, Blay JY, Rüttinger D | title = Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy | journal = Cancer Cell | volume = 25 | issue = 6 | pages = 846–859 | date = June 2014 | pmid = 24898549 | doi = 10.1016/j.ccr.2014.05.016 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ruffell B, Coussens LM | title = Macrophages and therapeutic resistance in cancer | journal = Cancer Cell | volume = 27 | issue = 4 | pages = 462–472 | date = April 2015 | pmid = 25858805 | pmc = 4400235 | doi = 10.1016/j.ccell.2015.02.015 }}</ref> However, macrophages are also involved in antibody mediated cytotoxicity (ADCC) and this mechanism has been proposed to be important for certain cancer immunotherapy antibodies.<ref>{{cite journal | vauthors = Sharma N, Vacher J, Allison JP | title = TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 21 | pages = 10453–10462 | date = May 2019 | pmid = 31076558 | pmc = 6534983 | doi = 10.1073/pnas.1819004116 | bibcode = 2019PNAS..11610453S | doi-access = free }}</ref> Similarly, studies identified macrophages genetically engineered to express chimeric antigen receptors as promising therapeutic approach to lowering tumor burden.<ref>{{Cite journal |last1=Klichinsky |first1=Michael |last2=Ruella |first2=Marco |last3=Shestova |first3=Olga |last4=Lu |first4=Xueqing Maggie |last5=Best |first5=Andrew |last6=Zeeman |first6=Martha |last7=Schmierer |first7=Maggie |last8=Gabrusiewicz |first8=Konrad |last9=Anderson |first9=Nicholas R. |last10=Petty |first10=Nicholas E. |last11=Cummins |first11=Katherine D. |last12=Shen |first12=Feng |last13=Shan |first13=Xinhe |last14=Veliz |first14=Kimberly |last15=Blouch |first15=Kristin |date=August 2020 |title=Human chimeric antigen receptor macrophages for cancer immunotherapy |journal=Nature Biotechnology |language=en |volume=38 |issue=8 |pages=947–953 |doi=10.1038/s41587-020-0462-y |pmid=32361713 |pmc=7883632 |issn=1087-0156}}</ref>

=== Obesity ===
It has been observed that increased number of pro-inflammatory macrophages within obese adipose tissue contributes to obesity complications including insulin resistance and diabetes type 2.<ref>Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue" ''Journal of Clinical Investigation'' 2003; 112:1796–808.</ref>

The modulation of the inflammatory state of adipose tissue macrophages has therefore been considered a possible therapeutic target to treat obesity-related diseases.<ref>{{cite journal | vauthors = Guilherme A, Henriques F, Bedard AH, Czech MP | title = Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus | journal = Nature Reviews. Endocrinology | volume = 15 | issue = 4 | pages = 207–225 | date = April 2019 | pmid = 30733616 | pmc = 7073451 | doi = 10.1038/s41574-019-0165-y }}</ref> Although adipose tissue macrophages are subject to anti-inflammatory homeostatic control by sympathetic innervation, experiments using [[Beta-2 adrenergic receptor|ADRB2 gene]] knockout mice indicate that this effect is indirectly exerted through the modulation of adipocyte function, and not through direct [[Beta-2 adrenergic receptor]] activation, suggesting that adrenergic stimulation of macrophages may be insufficient to impact adipose tissue inflammation or function in obesity.<ref>{{cite journal | vauthors = Petkevicius K, Bidault G, Virtue S, Newland SA, Dale M, Dugourd A, Saez-Rodriguez J, Mallat Z, Vidal-Puig A | title = Macrophage beta2-adrenergic receptor is dispensable for the adipose tissue inflammation and function | journal = Molecular Metabolism | volume = 48 | pages = 101220 | date = June 2021 | pmid = 33774223 | pmc = 8086137 | doi = 10.1016/j.molmet.2021.101220 | doi-access = free }}</ref>

Within the fat ([[Adipose tissue|adipose]]) tissue of [[CCR2]] deficient [[Mouse|mice]], there is an increased number of [[eosinophil]]s, greater alternative macrophage activation, and a propensity towards type 2 [[cytokine]] expression. Furthermore, this effect was exaggerated when the mice became [[Obesity|obese]] from a high fat diet.<ref>{{cite journal | vauthors = Bolus WR, Gutierrez DA, Kennedy AJ, Anderson-Baucum EK, Hasty AH | title = CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue | journal = Journal of Leukocyte Biology | volume = 98 | issue = 4 | pages = 467–477 | date = October 2015 | pmid = 25934927 | pmc = 4763864 | doi = 10.1189/jlb.3HI0115-018R }}</ref> This is partially caused by a phenotype switch of macrophages induced by [[necrosis]] of fat cells ([[adipocyte]]s). In an obese individual some adipocytes burst and undergo necrotic death, which causes the residential M2 macrophages to switch to M1 phenotype. This is one of the causes of a low-grade systemic chronic inflammatory state associated with obesity.<ref>{{cite journal | vauthors = Boutens L, Stienstra R | title = Adipose tissue macrophages: going off track during obesity | journal = Diabetologia | volume = 59 | issue = 5 | pages = 879–894 | date = May 2016 | pmid = 26940592 | pmc = 4826424 | doi = 10.1007/s00125-016-3904-9 }}</ref><ref>{{cite journal | vauthors = Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS | title = Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans | journal = Journal of Lipid Research | volume = 46 | issue = 11 | pages = 2347–2355 | date = November 2005 | pmid = 16150820 | doi = 10.1194/jlr.M500294-JLR200 | doi-access = free }}</ref>