Induction of ER stress in macrophages of tuberculosis granulomas

 

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dc.contributor.author Seimon, Tracie A en_ZA
dc.contributor.author Kim, Mi-Jeong en_ZA
dc.contributor.author Blumenthal, Antje en_ZA
dc.contributor.author Koo, Jovanka en_ZA
dc.contributor.author Ehrt, Sabine en_ZA
dc.contributor.author Wainwright, Helen en_ZA
dc.contributor.author Bekker, Linda-Gail en_ZA
dc.contributor.author Kaplan, Gilla en_ZA
dc.contributor.author Nathan, Carl en_ZA
dc.contributor.author Tabas, Ira en_ZA
dc.date.accessioned 2015-12-20T16:03:53Z
dc.date.available 2015-12-20T16:03:53Z
dc.date.issued 2010 en_ZA
dc.identifier.citation Seimon, Tracie A., Mi-Jeong Kim, Antje Blumenthal, Jovanka Koo, Sabine Ehrt, Helen Wainwright, Linda-Gail Bekker et al. "Induction of ER stress in macrophages of tuberculosis granulomas." PLoS One 5, no. 9 (2010): e12772-e12772. doi:10.1371/journal.pone.0012772 en_ZA
dc.identifier.uri http://hdl.handle.net/11427/15910
dc.identifier.uri http://dx.doi.org/10.1371/journal.pone.0012772
dc.description.abstract BACKGROUND: The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection. Principal FINDINGS: Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb) . These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation. CONCLUSIONS: In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection. en_ZA
dc.language.iso eng en_ZA
dc.publisher Public Library of Science en_ZA
dc.rights This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. en_ZA
dc.rights.uri http://creativecommons.org/licenses/by/4.0 en_ZA
dc.source PLoS One en_ZA
dc.source.uri http://journals.plos.org/plosone en_ZA
dc.subject.other Apoptosis en_ZA
dc.subject.other Macrophages en_ZA
dc.subject.other Granulomas en_ZA
dc.subject.other Mycobacterium tuberculosis en_ZA
dc.subject.other Tuberculosis en_ZA
dc.subject.other DAPI staining en_ZA
dc.subject.other Hematoxylin staining en_ZA
dc.subject.other Endoplasmic reticulum en_ZA
dc.title Induction of ER stress in macrophages of tuberculosis granulomas en_ZA
dc.type Journal Article en_ZA
dc.rights.holder © 2010 Seimon et al en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Desmond Tutu HIV Centre en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Seimon, T. A., Kim, M., Blumenthal, A., Koo, J., Ehrt, S., Wainwright, H., ... Tabas, I. (2010). Induction of ER stress in macrophages of tuberculosis granulomas. <i>PLoS One</i>, http://hdl.handle.net/11427/15910 en_ZA
dc.identifier.chicagocitation Seimon, Tracie A, Mi-Jeong Kim, Antje Blumenthal, Jovanka Koo, Sabine Ehrt, Helen Wainwright, Linda-Gail Bekker, Gilla Kaplan, Carl Nathan, and Ira Tabas "Induction of ER stress in macrophages of tuberculosis granulomas." <i>PLoS One</i> (2010) http://hdl.handle.net/11427/15910 en_ZA
dc.identifier.vancouvercitation Seimon TA, Kim M, Blumenthal A, Koo J, Ehrt S, Wainwright H, et al. Induction of ER stress in macrophages of tuberculosis granulomas. PLoS One. 2010; http://hdl.handle.net/11427/15910. en_ZA
dc.identifier.ris TY - Journal Article AU - Seimon, Tracie A AU - Kim, Mi-Jeong AU - Blumenthal, Antje AU - Koo, Jovanka AU - Ehrt, Sabine AU - Wainwright, Helen AU - Bekker, Linda-Gail AU - Kaplan, Gilla AU - Nathan, Carl AU - Tabas, Ira AB - BACKGROUND: The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection. Principal FINDINGS: Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb) . These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation. CONCLUSIONS: In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection. DA - 2010 DB - OpenUCT DO - 10.1371/journal.pone.0012772 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2010 T1 - Induction of ER stress in macrophages of tuberculosis granulomas TI - Induction of ER stress in macrophages of tuberculosis granulomas UR - http://hdl.handle.net/11427/15910 ER - en_ZA


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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.